Thiazolyl piperidine derivatives

ABSTRACT

The present invention relates to compounds of formula I 
                         
wherein R 1 , R 2  and R 3  are as defined in the description and claims. It further relates to pharmaceutically acceptable salts thereof as well as to pharmaceutical compositions comprising these compounds and to methods for their preparation. The compounds are useful for the treatment and/or prevention of diseases which are associated with the modulation of H3 receptors.

PRIORITY TO RELATED APPLICATIONS

This application claims the benefit of European Application No.05107586.9, filed Aug. 18, 2005, which is hereby incorporated byreference in its entirety.

FIELD OF THE INVENTION

The present invention is concerned with novel thiazol-2-yl-piperidinederivatives, their manufacture, pharmaceutical compositions containingthem and their use as medicaments. The active compounds of the presentinvention are useful in treating obesity and other disorders.

In particular, the present invention relates to compounds of the generalformula

and pharmaceutically acceptable salts thereof.

The compounds of formula I are antagonists and/or inverse agonists atthe histamine 3 receptor (H3 receptor).

All documents cited or relied upon below are expressly incorporatedherein by reference.

BACKGROUND

Histamine (2-(4-imidazolyl)ethylamine) is one of the aminergicneurotransmitters which is widely distributed throughout the body, e. g.the gastrointestinal tract (Burks 1994 in Johnson L. R. ed., Physiologyof the Gastrointestinal Tract, Raven Press, NY, pp. 211-242). Histamineregulates a variety of digestive pathophysiological events like gastricacid secretion, intestinal motility (Leurs et al., Br J. Pharmacol.1991, 102, pp 179-185), vasomotor responses, intestinal inflammatoryresponses and allergic reactions (Raithel et al., Int. Arch. AllergyImmunol. 1995, 108, 127-133). In the mammalian brain, histamine issynthesized in histaminergic cell bodies which are found centrally inthe tuberomammillary nucleus of the posterior basal hypothalamus. Fromthere, the histaminergic cell bodies project to various brain regions(Panula et al., Proc. Natl. Acad. Sci. USA 1984, 81, 2572-2576; Inagakiet al., J. Comp. Neurol 1988, 273, 283-300).

According to current knowledge, histamine mediates all its actions inboth the CNS and the periphery through four distinct histaminereceptors, the histamine H1, H2, H3 and H4 receptors.

H3 receptors are predominantly localized in the central nervous system(CNS). As an autoreceptor H3 receptors constitutively inhibit thesynthesis and secretion of histamine from histaminergic neurons (Arranget al., Nature 1983, 302, 832-837; Arrang et al., Neuroscience 1987, 23,149-157). As heteroreceptors, H3 receptors also modulate the release ofother neurotransmitters such as acetylcholine, dopamine, serotonin andnorepinephrine among others in both the central nervous system and inperipheral organs, such as lungs, cardiovascular system andgastrointestinal tract (Clapham & Kilpatrik, Br. J. Pharmacol. 1982,107, 919-923; Blandina et al. in The Histamine H3 Receptor (Leurs R Land Timmermann H eds, 1998, pp 27-40, Elsevier, Amsterdam, TheNetherlands). H3 receptors are constitutively active, meaning that evenwithout exogenous histamine, the receptor is tonically activated. In thecase of an inhibitory receptor such as the H3 receptor, this inherentactivity causes tonic inhibition of neurotransmitter release. Thereforeit may be important that a H3R antagonist would also have inverseagonist activity to both block exogenous histamine effects and to shiftthe receptor from its constitutively active (inhibitory) form to aneutral state.

The wide distribution of H3 receptors in the mammalian CNS indicates thephysiological role of this receptor. Therefore the therapeutic potentialas a novel drug development target in various indications has beenproposed.

The administration of H3R ligands—as antagonists, inverse agonists,agonists or partial agonists—may influence the histamine levels or thesecretion of neurotransmitters in the brain and the periphery and thusmay be useful in the treatment of several disorders. Such disordersinclude obesity, (Masaki et al; Endocrinol. 2003, 144, 2741-2748;Hancock et al., European J. of Pharmacol. 2004, 487, 183-197),cardiovascular disorders such as acute myocardial infarction, dementiaand cognitive disorders such as attention deficit hyperactivity disorder(ADHD) and Alzheimer's disease, neurological disorders such asschizophrenia, depression, epilepsy, Parkinson's disease, and seizuresor convulsions, sleep disorders, narcolepsy, pain, gastrointestinaldisorders, vestibular dysfunction such as Morbus Meniere, drug abuse andmotion sickness (Timmermann, J. Med. Chem. 1990, 33, 4-11).

SUMMARY OF THE INVENTION

In one embodiment of the present invention, provided is a compound ofthe formula:

wherein

-   -   R¹ is selected from the group consisting of    -   phenyl unsubstituted or substituted with one or two groups        independently selected from the group consisting of lower alkyl,        halogen, lower halogenalkyl, lower alkoxy, lower halogenalkoxy,        cyano, pyrrolyl and lower hydroxyalkyl, tetrahydronaphthalenyl        unsubstituted or substituted with one to four groups        independently selected from the group consisting of lower alkyl,        halogen, lower halogenalkyl, lower alkoxy, lower halogenalkoxy,        cyano, pyrrolyl and lower hydroxyalkyl;    -   benzo[1,3]dioxolyl,    -   benzo[1,4]dioxepinyl,    -   cycloalkyl,    -   pyridyl unsubstituted or substituted with one or two groups        independently selected from the group consisting of lower alkyl,        halogen, lower halogenalkyl, lower alkoxy, lower halogenalkoxy,        cyano, pyrrolyl and lower hydroxyalkyl, pyrazinyl unsubstituted        or substituted with one or two groups independently selected        from the group consisting of lower alkyl, halogen, lower        halogenalkyl, lower alkoxy, lower halogenalkoxy, cyano, pyrrolyl        and lower hydroxyalkyl, thienyl unsubstituted or substituted        with one or two groups independently selected from the group        consisting of lower alkyl, halogen, lower halogenalkyl, lower        alkoxy, lower halogenalkoxy, cyano, pyrrolyl and lower        hydroxyalkyl, and —CO—NR⁴R⁵, wherein    -   R⁴ is hydrogen or lower alkyl,    -   R⁵ is phenyl unsubstituted or substituted with one or two groups        independently selected from the group consisting of lower alkyl,        halogen, lower alkoxy and lower hydroxyalkyl, or    -   R⁴ and R⁵ together with the nitrogen atom to which they are        attached form a 4-, 5-, 6- or 7-membered saturated or partly        unsaturated heterocyclic ring optionally containing a further        heteroatom selected from nitrogen, oxygen or sulfur, said        saturated heterocyclic ring    -   being unsubstituted or substituted by one, two or three groups        independently selected from the group consisting of lower alkyl,        halogen, halogenalkyl, hydroxy, lower hydroxyalkyl, lower        alkoxy, oxo, phenyl, benzyl, pyridyl, dialkylamino, carbamoyl,        lower alkylsulfonyl, and lower halogenalkylcarbonylamino, or        being condensed with a phenyl ring, said phenyl ring being        unsubstituted or substituted by one, two or three groups        independently selected from lower alkyl, lower alkoxy and        halogen;    -   R² is hydrogen or lower alkyl;    -   R³ is C₃-C₈-alkyl or cycloalkyl;        and pharmaceutically acceptable salts thereof.

In another embodiment of the present invention, provided is a processfor the manufacture of a compound according to formula I, comprising thesteps of:

reacting a compound of the formula II

wherein R¹ and R² are as defined above, with an aldehyde or ketone ofthe formula IIIR′R″C═O  IIIwherein R′ is C₁-C₇-alkyl and R″ is C₁-C₆-alkyl or hydrogen or whereinR′ and R″ together with the C atom they are attached to form acycloalkyl ring, to obtain a compound of the formula I

wherein R¹, R² and R³ are as defined above, and if desired, convertingthe compound obtained into a pharmaceutically acceptable salt.

In a further embodiment of the present invention, provided is a processfor the manufacture of a compound according to formula I, wherein R¹ is—CO—NR⁴R⁵ and R⁴ and R⁵ are as defined above, comprising the steps of:

coupling a compound of the formula IV

wherein R² and R³ are as defined above, with an amine of formula VR⁴R⁵N—H  Vwherein R⁴ and R⁵ are as defined above,to obtain a compound of the formula I-A

wherein R¹ to R⁵ are as defined above,and if desired,converting the compound obtained into a pharmaceutically acceptablesalt.

In a still another embodiment of the present invention, provided is apharmaceutical composition, comprising a therapeutically effectiveamount of a compound according to formula I and a pharmaceuticallyacceptable carrier and/or adjuvant.

In a yet further embodiment of the present invention, provided is amethod for the treatment and/or prevention of diseases which areassociated with the modulation of H3 receptors, comprising the step ofadministering a therapeutically effective amount of a compound accordingto formula I to a human being or animal in need thereof.

In a still further embodiment of the present invention, provided is amethod for the treatment or prevention of obesity in a human being oranimal, comprising the step of administering to said human being oranimal in need thereof a therapeutically effective amount of a compoundaccording to formula I in combination or association with atherapeutically effective amount of a compound selected from the groupconsisting of a lipase inhibitor, an anorectic agent, a selectiveserotonin reuptake inhibitor, and an agent that stimulates metabolism ofbody fat.

In a yet another embodiment of the present invention, provided is amethod of treatment or prevention of type II diabetes in a human beingor animal, comprising the step of administering to said human being oranimal in need thereof a therapeutically effective amount of a compoundaccording to formula I in combination or association with atherapeutically effective amount of an anti-diabetic agent.

DETAILED DESCRIPTION

The invention provides for selective, directly acting H3 receptorantagonists respectively inverse agonists. Such antagonists/inverseagonists are useful as therapeutically active substances, particularlyin the treatment and/or prevention of diseases which are associated withthe modulation of H3 receptors.

In the present description the term “alkyl”, alone or in combinationwith other groups, refers to a branched or straight-chain monovalentsaturated aliphatic hydrocarbon radical of one to twenty carbon atoms,preferably one to sixteen carbon atoms, more preferably one to tencarbon atoms.

The term “lower alkyl” or “C₁-C₈-alkyl”, alone or in combination,signifies a straight-chain or branched-chain alkyl group with 1 to 8carbon atoms, preferably a straight or branched-chain alkyl group with 1to 6 carbon atoms and particularly preferred a straight orbranched-chain alkyl group with 1 to 4 carbon atoms Examples ofstraight-chain and branched C₁-C₈ alkyl groups are methyl, ethyl,propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyls,the isomeric hexyls, the isomeric heptyls and the isomeric octyls,preferably methyl and ethyl and most preferred methyl.

The term “cycloalkyl” or “C₃₋₇-cycloalkyl” denotes a saturatedcarbocyclic group containing from 3 to 7 carbon atoms, such ascyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.Especially preferred are cyclopropyl, cyclopentyl and cyclohexyl withcyclopentyl being particularly preferred.

The term “lower alkoxy” refers to the group R′—O—, wherein R′ is loweralkyl and the term “lower alkyl” has the previously given significance.Examples of lower alkoxy groups are e.g. methoxy, ethoxy, n-propoxy,isopropoxy, n-butoxy, isobutoxy, sec. butoxy and tert.butoxy, preferablymethoxy and ethoxy and most preferred methoxy.

The term “alkylsulfonyl” or “lower alkylsulfanyl” refers to the groupR′—S(O)₂-, wherein R′ is lower alkyl and the term “lower alkyl” has thepreviously given significance. Examples of alkylsulfonyl groups are e.g.methylsulfonyl or ethylsulfonyl.

The term “halogen” refers to fluorine, chlorine, bromine and iodine,with fluorine, chlorine and bromine being preferred.

The term “lower halogenalkyl” or “halogen-C₁₋₈-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a halogen atom, preferablyfluoro or chloro, most preferably fluoro. Among the preferredhalogenated lower alkyl groups are trifluoromethyl, difluoromethyl,fluoromethyl and chloromethyl, with trifluoromethyl being especiallypreferred.

The term “lower halogenalkoxy” or “halogen-C₁₋₈-alkoxy” refers to loweralkoxy groups as defined above wherein at least one of the hydrogenatoms of the lower alkoxy group is replaced by a halogen atom,preferably fluoro or chloro, most preferably fluoro. Among the preferredhalogenated lower alkyl groups are trifluoromethoxy, difluoromethoxy,fluormethoxy and chloromethoxy, with trifluoromethoxy being especiallypreferred.

The term “lower hydroxyalkyl” or “hydroxy-C₁₋₈-alkyl” refers to loweralkyl groups as defined above wherein at least one of the hydrogen atomsof the lower alkyl group is replaced by a hydroxy group. Examples oflower hydroxyalkyl groups are hydroxymethyl or hydroxyethyl.

The term “dialkylamino” refers to the group —NR′R″, wherein R′ and R″are lower alkyl and the term “lower alkyl” has the previously givensignificance. A preferred dialkylamino group is dimethylamino.

The term “form a 4-, 5-, 6- or 7-membered saturated heterocyclic ringoptionally containing a further heteroatom selected from nitrogen,oxygen or sulfur” refers to a saturated N-heterocyclic ring, which mayoptionally contain a further nitrogen, oxygen or sulfur atom, such asazetidinyl, pyrrolidinyl, imidazolidinyl, pyrazolidinyl, oxazolidinyl,isoxazolidinyl, thiazolidinyl, isothiazolidinyl, piperidinyl,piperazinyl, morpholinyl, thiomorpholinyl, or azepanyl. A “4-, 5-, 6- or7-membered partly unsaturated heterocyclic ring” means a heterocyclicring as defined above which contains a double bond, for example2,5-dihydropyrrolyl or 3,6-dihydro-2H-pyridinyl. The heteroyclic ringmay be unsubstituted or substituted by one, two or three groupsindependently selected from the group consisting of lower alkyl,halogen, halogenalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo,phenyl, benzyl, pyridyl, dialkylamino, carbamoyl, lower alkylsulfonyl,and lower halogenalkylcarbonylamino. The heterocyclic ring may also becondensed with a phenyl ring, said phenyl ring being unsubstituted orsubstituted by one, two or three groups independently selected fromlower alkyl, lower alkoxy and halogen. An example for such a condensedheterocyclic ring is 3,4-dihydro-1H-isoquinoline.

The term “pharmaceutically acceptable salts” refers to those salts whichretain the biological effectiveness and properties of the free bases orfree acids, which are not biologically or otherwise undesirable. Thesalts are formed with inorganic acids such as hydrochloric acid,hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and thelike, preferably hydrochloric acid, and organic acids such as aceticacid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleicacid, malonic acid, salicylic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, N-acetylcystein and the like. In addition these saltsmay be prepared form addition of an inorganic base or an organic base tothe free acid. Salts derived from an inorganic base include, but are notlimited to, the sodium, potassium, lithium, ammonium, calcium, magnesiumsalts and the like. Salts derived from organic bases include, but arenot limited to salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, such as isopropylamine,trimethylamine, diethylamine, triethylamine, tripropylamine,ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymineresins and the like. The compound of formula I can also be present inthe form of zwitterions. Particularly preferred pharmaceuticallyacceptable salts of compounds of formula I are the hydrochloride salts.

The compounds of formula I can also be solvated, e.g. hydrated. Thesolvation can be effected in the course of the manufacturing process orcan take place e.g. as a consequence of hygroscopic properties of aninitially anhydrous compound of formula I (hydration). The termpharmaceutically acceptable salts also includes physiologicallyacceptable solvates.

“Isomers” are compounds that have identical molecular formulae but thatdiffer in the nature or the sequence of bonding of their atoms or in thearrangement of their atoms in space. Isomers that differ in thearrangement of their atoms in space are termed “stereoisomers”.Stereoisomers that are not mirror images of one another are termed“diastereoisomers”, and stereoisomers that are non-superimposable mirrorimages are termed “enantiomers”, or sometimes optical isomers. A carbonatom bonded to four nonidentical substituents is termed a “chiralcenter”.

In detail, the present invention relates to compounds of the generalformula

wherein

-   -   R¹ is selected from the group consisting of    -   phenyl unsubstituted or substituted with one or two groups        independently selected from the group consisting of lower alkyl,        halogen, lower halogenalkyl, lower alkoxy, lower halogenalkoxy,        cyano, pyrrolyl and lower hydroxyalkyl, tetrahydronaphthalenyl        unsubstituted or substituted with one to four groups        independently selected from the group consisting of lower alkyl,        halogen, lower halogenalkyl, lower alkoxy, lower halogenalkoxy,        cyano, pyrrolyl and lower hydroxyalkyl;    -   benzo[1,3]dioxolyl,    -   benzo[1,4]dioxepinyl,    -   cycloalkyl,    -   pyridyl unsubstituted or substituted with one or two groups        independently selected from the group consisting of lower alkyl,        halogen, lower halogenalkyl, lower alkoxy, lower halogenalkoxy,        cyano, pyrrolyl and lower hydroxyalkyl, pyrazinyl unsubstituted        or substituted with one or two groups independently selected        from the group consisting of lower alkyl, halogen, lower        halogenalkyl, lower alkoxy, lower halogenalkoxy, cyano, pyrrolyl        and lower hydroxyalkyl, thienyl unsubstituted or substituted        with one or two groups independently selected from the group        consisting of lower alkyl, halogen, lower halogenalkyl, lower        alkoxy, lower halogenalkoxy, cyano, pyrrolyl and lower        hydroxyalkyl, and —CO—NR⁴R⁵, wherein    -   R⁴ is hydrogen or lower alkyl,    -   R⁵ is phenyl unsubstituted or substituted with one or two groups        independently selected from the group consisting of lower alkyl,        halogen, lower alkoxy and lower hydroxyalkyl, or    -   R⁴ and R⁵ together with the nitrogen atom to which they are        attached form a 4-, 5-, 6- or 7-membered saturated or partly        unsaturated heterocyclic ring optionally containing a further        heteroatom selected from nitrogen, oxygen or sulfur, said        saturated heterocyclic ring    -   being unsubstituted or substituted by one, two or three groups        independently selected from the group consisting of lower alkyl,        halogen, halogenalkyl, hydroxy, lower hydroxyalkyl, lower        alkoxy, oxo, phenyl, benzyl, pyridyl, dialkylamino, carbamoyl,        lower alkylsulfonyl, and lower halogenalkylcarbonylamino, or        being condensed with a phenyl ring, said phenyl ring being        unsubstituted or substituted by one, two or three groups        independently selected from lower alkyl, lower alkoxy and        halogen;    -   R² is hydrogen or lower alkyl;    -   R³ is C₃-C₈-alkyl or cycloalkyl;        and pharmaceutically acceptable salts thereof.

In one embodiment, the invention relates to compounds of formula I,wherein R¹ is selected from the group consisting of

-   phenyl unsubstituted or substituted with one or two groups    independently selected from the group consisting of lower alkyl,    halogen, lower halogenalkyl, lower alkoxy, lower halogenalkoxy,    cyano, pyrrolyl and lower hydroxyalkyl,-   tetrahydronaphthalenyl unsubstituted or substituted with one to four    groups independently selected from the group consisting of lower    alkyl, halogen, lower halogenalkyl, lower alkoxy, lower    halogenalkoxy, cyano, pyrrolyl and lower hydroxyalkyl;-   benzo[1,3]dioxolyl,-   benzo[1,4]dioxepinyl,-   cycloalkyl,-   pyridyl unsubstituted or substituted with one or two groups    independently selected from the group consisting of lower alkyl,    halogen, lower halogenalkyl, lower alkoxy, lower halogenalkoxy,    cyano, pyrrolyl and lower hydroxyalkyl,-   pyrazinyl unsubstituted or substituted with one or two groups    independently selected from the group consisting of lower alkyl,    halogen, lower halogenalkyl, lower alkoxy, lower halogenalkoxy,    cyano, pyrrolyl and lower hydroxyalkyl, and-   thienyl unsubstituted or substituted with one or two groups    independently selected from the group consisting of lower alkyl,    halogen, lower halogenalkyl, lower alkoxy, lower halogenalkoxy,    cyano, pyrrolyl and lower hydroxyalkyl.

Preferred compounds of formula I of the present invention are compoundsof formula I, wherein R¹ is phenyl unsubstituted or substituted with oneor two groups independently selected from the group consisting of loweralkyl, halogen, lower halogenalkyl, lower alkoxy, lower halogenalkoxy,cyano, pyrrolyl and lower hydroxyalkyl.

More preferred are compounds of formula I, wherein R¹ is phenylsubstituted with one or two groups independently selected from the groupconsisting of lower alkyl, halogen, lower halogenalkyl, lower alkoxy,lower halogenalkoxy, cyano, pyrrolyl and lower hydroxyalkyl.

Especially preferred are compounds of formula I, wherein R¹ is phenylsubstituted with one or two groups independently selected from the groupconsisting of halogen, lower alkoxy, lower halogenalkoxy and pyrrolyl,with those compounds, wherein R¹ is phenyl substituted with one or twogroups selected from lower alkoxy or lower halogenalkoxy, being mostpreferred.

In a further embodiment, the invention relates to compounds of formula Ias described herein before, wherein R¹ is —CO—NR⁴R⁵ and wherein

-   R⁴ is hydrogen or lower alkyl,-   R⁵ is phenyl unsubstituted or substituted with one or two groups    independently selected from the group consisting of lower alkyl,    halogen, lower alkoxy and lower hydroxyalkyl, or-   R⁴ and R⁵ together with the nitrogen atom to which they are attached    form a 4-, 5-, 6- or 7-membered saturated or partly unsaturated    heterocyclic ring optionally containing a further heteroatom    selected from nitrogen, oxygen or sulfur,-   said saturated heterocyclic ring-   being unsubstituted or substituted by one, two or three groups    independently selected from the group consisting of lower alkyl,    halogen, halogenalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy,    oxo, phenyl, benzyl, pyridyl, dialkylamino, carbamoyl, lower    alkylsulfonyl, and lower halogenalkylcarbonylamino, or-   being condensed with a phenyl ring, said phenyl ring being    unsubstituted or substituted by one, two or three groups    independently selected from lower alkyl, lower alkoxy and halogen.

Especially preferred are those compounds of formula I, wherein R¹ is—CO—NR⁴R⁵ and wherein R⁴ and R⁵ together with the nitrogen atom to whichthey are attached form a 4-, 5-, 6- or 7-membered saturated or partlyunsaturated heterocyclic ring optionally containing a further heteroatomselected from nitrogen, oxygen or sulfur, said saturated heterocyclicring being unsubstituted or substituted by one, two or three groupsindependently selected from the group consisting of lower alkyl,halogen, halogenalkyl, hydroxy, lower hydroxyalkyl, lower alkoxy, oxo,phenyl, benzyl, pyridyl, dialkylamino, carbamoyl, lower alkylsulfonyl,and lower halogenalkylcarbonylamino, or being condensed with a phenylring, said phenyl ring being unsubstituted or substituted by one, two orthree groups independently selected from lower alkyl, lower alkoxy andhalogen.

Even more preferably, R⁴ and R⁵ together with the nitrogen atom to whichthey are attached form a heterocyclic ring selected from the groupconsisting of morpholine, piperidine, azepane, pyrrolidine, azetidineand 3,4-dihydro-1H-isoquinoline, wherein the ring is unsubstituted orsubstituted by lower alkyl.

Also preferred are compounds of formula I, wherein R¹ is —CO—NR⁴R⁵ andwherein R⁴ is hydrogen and R⁵ is phenyl unsubstituted or substitutedwith one or two groups independently selected from the group consistingof lower alkyl, halogen, lower alkoxy and lower hydroxyalkyl, with thosecompounds wherein R⁵ is phenyl substituted by halogen or lower alkoxybeing especially preferred.

Furthermore, compounds of formula I according to the present inventionare preferred, wherein R² is hydrogen.

Also preferred are compounds of formula, wherein R² is lower alkyl, withthose compounds wherein R² is methyl being especially preferred.

Another group of preferred compounds of formula I are those, wherein R³is C₃-C₈-alkyl.

Especially preferred are compounds of formula I, wherein R³ is isopropylor isobutyl.

Also preferred are compounds of formula I, wherein R³ is cycloalkyl,with those compounds, wherein R³ is cyclopentyl being especiallypreferred.

Examples of preferred compounds of formula I are the following:

-   -   isopropyl-4-(4-phenyl-thiazol-2-yl)-piperidine,

-   cyclopentyl-4-(4-phenyl-thiazol-2-yl)-piperidine,

-   4-[4-(3,4-difluoro-phenyl)-thiazol-2-yl]-1-isobutyl-piperidine,

-   4-[4-(3,4-difluoro-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine,

-   cyclopentyl-4-[4-(3,4-difluoro-phenyl)-thiazol-2-yl]-piperidine,

-   4-(4-cyclohexyl-thiazol-2-yl)-1-isobutyl-piperidine,

-   4-(4-cyclohexyl-thiazol-2-yl)-1-cyclopentyl-piperidine,

-   isobutyl-4-[4-(4-methoxy-phenyl)-thiazol-2-yl]-piperidine,

-   isopropyl-4-[4-(4-methoxy-phenyl)-thiazol-2-yl]-piperidine,

-   cyclopentyl-4-[4-(4-methoxy-phenyl)-thiazol-2-yl]-piperidine,

-   4-[4-(2-fluoro-4-methoxy-phenyl)-thiazol-2-yl]-1-isobutyl-piperidine,

-   4-[4-(2-fluoro-4-methoxy-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine

-   cyclopentyl-4-[4-(2-fluoro-4-methoxy-phenyl)-thiazol-2-yl]-piperidine,

-   isobutyl-4-[4-(2-methoxy-phenyl)-thiazol-2-yl]-piperidine,

-   isopropyl-4-[4-(2-methoxy-phenyl)-thiazol-2-yl]-piperidine,

-   cyclopentyl-4-[4-(2-methoxy-phenyl)-thiazol-2-yl]-piperidine,

-   2-[2-(1-isobutyl-piperidine-4-yl)-thiazol-4-yl]-3-methyl-pyrazine,

-   2-[2-(1-cyclopentyl-piperidin-4-yl)-thiazol-4-yl]-3-methyl-pyrazine,

-   isobutyl-4-[4-(2-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine,

-   cyclopentyl-4-[4-(2-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine,

-   4-[4-(4-chloro-phenyl)-thiazol-2-yl]-1-isobutyl-piperidine,

-   4-[4-(4-chloro-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine,

-   4-[4-(4-chloro-phenyl)-thiazol-2-yl]-1-cyclopentyl-piperidine,

-   4-[4-(3-fluoro-phenyl)-thiazol-2-yl]-1-isobutyl-piperidine,

-   4-[4-(3-fluoro-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine,

-   cyclopentyl-4-[4-(3-fluoro-phenyl)-thiazol-2-yl]-piperidine,

-   cyclopentyl-4-(5-methyl-4-phenyl-thiazol-2-yl)-piperidine,

-   4-[4-(2-fluoro-3-trifluoromethyl-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine,

-   4-[2-(1-isopropyl-piperidin-4-yl)-thiazol-4-yl]-benzonitrile,

-   isopropyl-4-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine,

-   isopropyl-4-[4-(3-methoxy-phenyl)-thiazol-2-yl]-piperidine,

-   isopropyl-4-(4-p-tolyl-thiazol-2-yl)-piperidine,

-   4-[4-(4-difluoromethoxy-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine,

-   4-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-thiazol-2-yl]-1-isopropyl-piperidine,

-   4-[4-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-thiazol-2-yl]-1-isopropyl-piperidine,

-   3-[2-(1-isopropyl-piperidin-4-yl)-thiazol-4-yl]-benzonitrile,

-   isopropyl-4-[4-(4-pyrrolidin-1-yl-phenyl)-thiazol-2-yl]-piperidine,

-   isopropyl-4-[4-(4-trifluoromethoxy-phenyl)-thiazol-2-yl]-piperidine,

-   isopropyl-4-[4-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine,

-   4-[4-(3,4-dimethoxy-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine,

-   4-(4-benzo[1,3]dioxol-5-yl-thiazol-2-yl-1-isopropyl-piperidine,

-   4-[4-(4-bromo-phenyl)-5-methyl-thiazol-2-yl]-1-isopropyl-piperidine,

-   isopropyl-4-(4-thiophen-3-yl-thiazol-2-yl)-piperidine,

-   isopropyl-4-(4-thiophen-2-yl-thiazol-2-yl)-piperidine,

-   4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine,

-   4-[4-(2,4-dimethoxy-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine,

-   4-[2-(1-cyclopentyl-piperidin-4-yl)-thiazol-4-yl]-benzonitrile,

-   cyclopentyl-4-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine,

-   cyclopentyl-4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-thiazol-2-yl]-piperidine,

-   cyclopentyl-4-[4-(3-methoxy-phenyl)-thiazol-2-yl]-piperidine,

-   cyclopentyl-4-[4-(4-difluoromethoxy-phenyl)-thiazol-2-yl]-piperidine,

-   cyclopentyl-4-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-thiazol-2-yl]-piperidine,

-   cyclopentyl-4-[4-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-thiazol-2-yl]-piperidine,

-   3-[2-(1-cyclopentyl-piperidin-4-yl)-thiazol-4-yl]-benzonitrile,

-   cyclopentyl-4-[4-(4-trifluoromethoxy-phenyl)-thiazol-2-yl]-piperidine,

-   cyclopentyl-4-[4-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine,

-   cyclopentyl-4-[4-(3,4-dimethoxy-phenyl)-thiazol-2-yl]-piperidine,

-   4-(4-benzo[1,3]dioxol-5-yl-thiazol-2-yl-1-cyclopentyl-piperidine,

-   4-[4-(4-bromo-phenyl)-5-methyl-thiazol-2-yl]-1-cyclopentyl-piperidine,

-   4-[2-(1-cyclopentyl-piperidin-4-yl)-thiazol-4-yl]-pyridine,

-   cyclopentyl-4-(4-thiophen-3-yl-thiazol-2-yl)-piperidine,

-   cyclopentyl-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-piperidine,

-   cyclopentyl-4-[4-(2,4-dimethoxy-phenyl)-thiazol-2-yl]-piperidine,

-   4-[4-(3,5-bis-trifluoromethyl-phenyl)-thiazol-2-yl]-1-cyclopentyl-piperidine,

-   2-(1-isopropyl-piperidin-4-yl)-thiazole-4-carboxylic acid    (4-chloro-phenyl)-amide,

-   [2-(1-cyclopentyl-piperidin-4-yl)-thiazol-4-yl]-(2-methyl-pyrrolidin-1-yl)-methanone,

-   [2-(1-cyclopentyl-piperidin-4-yl)-thiazol-4-yl]-(3-methyl-piperidin-1-yl)-methanone,

-   [2-(1-cyclopentyl-piperidin-4-yl)-thiazol-4-yl]-(2-methyl-piperidin-1-yl)-methanone,

-   azepan-1-yl-[2-(1-cyclopentyl-piperidin-4-yl)-thiazol-4-yl]-methanone,

-   [2-(1-cyclopentyl-piperidin-4-yl)-thiazol-4-yl]-(3,4-dihydro-1H-isoquinolin-2-yl)-methanone,

-   2-(1-cyclopentyl-piperidin-4-yl)-thiazole-4-carboxylic acid    phenylamide,

-   2-(1-cyclopentyl-piperidin-4-yl)-thiazole-4-carboxylic acid    (4-chloro-phenyl)-amide,

-   2-(1-cyclopentyl-piperidin-4-yl)-thiazole-4-carboxylic acid    (3-methoxy-phenyl)-amide,    and pharmaceutically acceptable salts thereof.

Especially preferred are the following compounds of formula I of thepresent invention:

-   isopropyl-4-[4-(4-methoxy-phenyl)-thiazol-2-yl]-piperidine,-   cyclopentyl-4-[4-(4-methoxy-phenyl)-thiazol-2-yl]-piperidine,-   4-[4-(2-fluoro-4-methoxy-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine-   cyclopentyl-4-[4-(2-fluoro-4-methoxy-phenyl)-thiazol-2-yl]-piperidine,-   cyclopentyl-4-[4-(2-methoxy-phenyl)-thiazol-2-yl]-piperidine,-   4-[4-(4-chloro-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine,-   4-[4-(4-chloro-phenyl)-thiazol-2-yl]-1-cyclopentyl-piperidine,-   isopropyl-4-[4-(4-pyrrolidin-1-yl-phenyl)-thiazol-2-yl]-piperidine,-   4-[4-(3,4-dimethoxy-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine,-   4-[4-(2,4-dimethoxy-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine,-   cyclopentyl-4-[4-(4-difluoromethoxy-phenyl)-thiazol-2-yl]-piperidine,-   4-[4-(4-bromo-phenyl)-5-methyl-thiazol-2-yl]-1-cyclopentyl-piperidine,-   cyclopentyl-4-[4-(2,4-dimethoxy-phenyl)-thiazol-2-yl]-piperidine,    and pharmaceutically acceptable salts thereof.

Furthermore, the pharmaceutically acceptable salts of the compounds offormula I and the pharmaceutically acceptable esters of the compounds offormula I individually constitute preferred embodiments of the presentinvention.

Compounds of formula I may form acid addition salts with acids, such asconventional pharmaceutically acceptable acids, for examplehydrochloride, hydrobromide, phosphate, acetate, fumarate, maleate,salicylate, sulphate, pyruvate, citrate, lactate, mandelate, tartarate,and methanesulphonate. Preferred are the hydrochloride salts. Alsosolvates and hydrates of compounds of formula I and their salts formpart of the present invention.

It will be appreciated, that the compounds of general formula I in thisinvention may be derivatized at functional groups to provide derivativeswhich are capable of conversion back to the parent compound in vivo.Physiologically acceptable and metabolically labile derivatives, whichare capable of producing the parent compounds of general formula I invivo are also within the scope of this invention.

A further aspect of the present invention is the process for themanufacture of compounds of formula I as defined above, which processcomprises reacting a compound of the formula II

wherein R¹ and R² are as defined herein before, preferably itshydrobromide salt, with an aldehyde or ketone of the formula IIIR′R″C═O  IIIwherein R′ is C₁-C₇-alkyl and R″ is C₁-C₆-alkyl or hydrogen or whereinR′ and R″ form together with the C atom they are attached to acycloalkyl ring, to obtain a compound of the formula I

wherein R¹, R² and R³ are as defined hereinbefore,and if desired,converting the compound obtained into a pharmaceutically acceptablesalt.

Preferred intermediate compounds of formula II are the following:

-   4-(phenylthiazol-2-yl)-piperidine hydrobromide,-   4-[4-(3,4-difluoro-phenyl)-thiazol-2-yl]-piperidine hydrobromide,-   4-(4-cyclohexyl-thiazol-2-yl)-piperidine hydrobromide,-   4-[4-(4-methoxy-phenyl)-thiazol-2-yl]-piperidine hydrobromide,-   4-[4-(2-fluoro-4-methoxy-phenyl)-thiazol-2-yl]-piperidine    hydrobromide,-   4-[4-(2-methoxy-phenyl)-thiazol-2-yl]-piperidine hydrobromide,-   2-methyl-3-(2-piperidin-4-yl-thiazol-4-yl)-pyrazine hydrobromide,-   4-[4-(2-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine    hydrobromide,-   4-[4-(4-chloro-phenyl)-thiazol-2-yl]-piperidine hydrobromide,-   4-[4-(3-fluoro-phenyl)-thiazol-2-yl]-piperidine hydrobromide,-   4-(5-methyl-4-phenyl-thiazol-2-yl)-piperidine hydrobromide,-   4-[4-(2-fluoro-3-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine    hydrobromide,-   4-(2-piperidin-4-yl-thiazol-4-yl)-benzonitrile hydrobromide,-   4-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine    hydrobromide,-   4-[4-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-thiazol-2-yl]-piperidine    hydrobromide,-   4-[4-(3-methoxy-phenyl)-thiazol-2-yl]-piperidine hydrobromide,-   4-(4-p-tolyl-thiazol-2-yl)-piperidine hydrobromide,-   4-[4-(4-difluoromethoxy-phenyl)-thiazol-2-yl]-piperidine    hydrobromide,-   4-[4-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-thiazol-2-yl]-piperidine    hydrobromide,-   4-[4-(3,4-dihydro-2H-benzo[b][1,4]dioxepin-7-yl)-thiazol-2-yl]-piperidine    hydrobromide,-   3-(2-piperidin-4-yl-thiazol-4-yl)-benzonitrile hydrobromide,-   4-[4-(4-pyrrolidin-1-yl-phenyl)-thiazol-2-yl]-piperidine    hydrobromide,-   4-[4-(4-trifluoromethoxy-phenyl)-thiazol-2-yl]-piperidine    hydrobromide,-   4-[4-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine    hydrobromide,-   4-[4-(3,4-dimethoxy-phenyl)-thiazol-2-yl]-piperidine hydrobromide,-   4-(4-benzo[1,3]dioxol-5-yl-thiazol-2-yl)-piperidine hydrobromide,-   4-[4-(4-bromo-phenyl)-5-methyl-thiazol-2-yl]-piperidine    hydrobromide,-   4-(2-piperidin-4-yl-thiazol-4-yl)-pyridine dihydrobromide,-   4-(4-thiophen-3-yl-thiazol-2-yl)-piperidine hydrobromide,-   4-(4-thiophen-2-yl-thiazol-2-yl)-piperidine hydrobromide,-   4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-piperidine hydrobromide,-   4-[4-(2,4-dimethoxy-phenyl)-thiazol-2-yl]-piperidine hydrobromide,    and-   4-[4-(3,5-bis-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine    hydrobromide.

A further aspect of the present invention is a process for themanufacture of compounds of formula I as defined above, wherein R¹ is—CO—NR⁴R⁵, which process comprises

-   -   coupling a compound of the formula IV

wherein R² and R³ are as defined herein before, with an amine of formulaVR⁴R⁵N—H  Vwherein R⁴ and R⁵ are as defined herein before, to obtain a compound ofthe formula I-A

wherein R¹ to R⁵ are as defined hereinbefore,and if desired,converting the compound obtained into a pharmaceutically acceptablesalt.

In more detail, the compounds of formula I can be manufactured by themethods given below, by the methods given in the examples or byanalogous methods. Appropriate reaction conditions for the individualreaction steps are known to a person skilled in the art. Startingmaterials are either commercially available or can be prepared bymethods analogous to the methods given below, by methods described inreferences cited in the text or in the examples, or by methods known inthe art.

The preparation of compounds of formula I of the present invention maybe carried out in sequential or convergent synthetic routes. Synthesesof the invention are shown in the following scheme. The skills requiredfor carrying out the reaction and purification of the resulting productsare known to those in the art. The substituents and indices used in thefollowing description of the processes have the significance given aboveunless indicated to the contrary.

Compounds of general formula I can be prepared according to scheme 1 asfollows: 4-Thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl esterVII (which is commercially available, CAS Registry No. 214834-18-1) canbe converted to thiazoles II by various procedures described in the art.However, it is convenient to react VII with α-bromo ketones (which areeither commercially available, described previously in the literature orsynthetically easily accessible via various routes described inliterature) in the presence or absence of a solvent and in the presenceor absence of a base. There is no particular restriction on the natureof the solvent to be employed, provided that it has no adverse effect onthe reaction or the reagents involved and that it can dissolve thereagents, at least to some extent. Examples for suitable solventsinclude: ethanol, methanol, dioxane, dimethylformamide and the like.There is no particular restriction on the nature of the base used inthis stage, and any base commonly used in this type of reaction mayequally be employed here. Examples of such bases include triethylamineand diisopropylethylamine, and the like. The reaction can take placeover a wide range of temperatures, and the precise reaction temperatureis not critical to the invention. It is convenient to carry out thereaction with heating from ambient temperature to reflux. The timerequired for the reaction may also vary widely, depending on manyfactors, notably the reaction temperature and the nature of thereagents. However, a period of from 0.5 h to several days will usuallysuffice to yield the thiazole derivatives II or the respective saltsthereof.

The alkylation of piperidine derivatives II can be carried out byvarious methods that are known to those in the art (For reactionconditions described in literature affecting such reactions see forexample: Comprehensive Organic Transformations: A Guide to FunctionalGroup Preparations, 2nd Edition, Richard C. Larock. John Wiley & Sons,New York, N.Y. 1999). For the reductive amination reducing agents suchas py-BH₃ complex, NaBH(OAc)₃, NaCNBH₃ can be employed under acidic(e.g. acetic acid additive, Ti(iPrO)₄, ZnCl₂) or under basic conditions(no additive) in a solvent such as dichloromethane (DCM), dichloroethane(DCE), tetrahydrofurane (THF), ethanol or mixtures thereof at ambient orelevated temperatures. It is convenient to react piperidine derivativesII with an excess amount of the appropriate aldehyde or ketone(commercially available) in the presence of an excess amount ofNaBH(OAc)₃ under acidic conditions (acetic acid). In cases where thepiperidines II were reacted with ketones the reaction temperature wasshifted from room temperature (used in the cases where piperidines IIwere reacted with aldehydes) to 40° C.

Compounds of formula I, wherein R¹ is —CO—NR⁴R⁵, are prepared from ethylbromopyruvates (VIII) following the method described in scheme 2.

4-Thiocarbamoyl-piperidine-1-carboxylic acid tert-butyl ester VII(commercially available) can be reacted with an ethyl bromopyruvate VIIIto obtain the thiazole derivatives IX. There is no particularrestriction on the nature of the solvent to be employed, provided thatit has no adverse effect on the reaction or the reagents involved andthat it can dissolve the reagents, at least to some extent. Examples forsuitable solvents include: ethanol, methanol, dioxane and the like. Thereaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. It isconvenient to carry out the reaction with heating from ambienttemperature to reflux.

The reductive amination of the piperidine can be carried out asdescribed in step b) above. It is convenient to react the piperidines IXwith an excess amount of the appropriate aldehyde or ketone(commercially available) in the presence of an excess amount ofNaBH(OAc)₃ under acidic conditions (acetic acid). In cases where anpiperidine IX is reacted with ketones the reaction temperature wasshifted from room temperature (used in the cases where piperidines IIwere reacted with aldehydes) to 40° C.

The esters of formula X can undergo consecutive reactions like cleavageof the ester moiety of X under various reaction conditions in order toaccess acid derivatives IV. However, it is convenient to react esters Xunder acidic conditions in the presence or absence of a solvent. Thereis no particular restriction on the nature of acids to be employed,provided that they affect the desired reaction. Examples for suitableacids include acetic acid, HCl and the like. There is no particularrestriction on the nature of the solvent to be employed, provided thatit has no adverse effect on the reaction or the reagents involved andthat it can dissolve the reagents, at least to some extent. Examples forsuitable solvents or mixtures thereof include: water, THF, dioxane andthe like. The reaction can take place over a wide range of temperatures,and the precise reaction temperature is not critical to the invention.It is convenient to carry out the reaction with heating from ambienttemperature to reflux. The time required for the reaction may also varywidely, depending on many factors, notably the reaction temperature andthe nature of the reagents. However, a period of from 0.5 h to severaldays will usually suffice to yield the acid derivatives IV.

The coupling of carboxylic acids with amines is widely described inliterature and the procedures are known to those in the art (Forreaction conditions described in literature affecting such reactions seefor example: Comprehensive Organic Transformations: A Guide toFunctional Group Preparations, 2nd Edition, Richard C. Larock. JohnWiley & Sons, New York, N.Y. 1999). Carboxylic acids IV can convenientlybe transformed to the respective amide through coupling with an amineHNR⁴R⁵ (V, either commercially available or accessible by methodsdescribed in references or by methods known in the art; as appropriate)by employing the usage of coupling reagents. For example coupling agentslike N,N′-carbonyldiimidazole (CDI), N,N′-dicyclohexylcarbodiimide(DCC), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDCI),1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxidehexafluorophosphate (HATU), 1-hydroxy-1,2,3-benzotriazole (HOBT),O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium tetrafluoroborate(TBTU) and the like can equally well be employed to affect suchtransformation. It is convenient to carry out the reaction in a solventlike dimethylformamide (DMF) and in the presence of a base. There is noparticular restriction on the nature of the solvent to be employed,provided that it has no adverse effect on the reaction or the reagentsinvolved and that it can dissolve the reagents, at least to some extent.Examples for suitable solvents include: DMF, dichloromethane (DCM),dioxane, THF, and the like. There is no particular restriction on thenature of the base used in this stage, and any base commonly used inthis type of reaction may equally be employed here. Examples of suchbases include triethylamine and diisopropylethylamine, and the like. Thereaction can take place over a wide range of temperatures, and theprecise reaction temperature is not critical to the invention. It isconvenient to carry out the reaction with heating from ambienttemperature to reflux. The time required for the reaction may also varywidely, depending on many factors, notably the reaction temperature andthe nature of the reagents. However, a period of from 0.5 h to severaldays will usually suffice to yield amide derivatives I-A.

As described above, the compounds of formula I of the present inventioncan be used as medicaments for the treatment and/or prevention ofdiseases which are associated with the modulation of H3 receptors.

In this context, the expression ‘diseases associated with the modulationof H3 receptors’ means diseases which can be treated and/or prevented bymodulation of H3 receptors. Examples of such diseases are obesity,metabolic syndrome (syndrome X), neurological diseases includingAlzheimer's disease, dementia, age-related memory dysfunction, mildcognitive impairment, cognitive deficit, attention deficit hyperactivitydisorder, epilepsy, neuropathic pain, inflammatory pain, migraine,Parkinson's disease, multiple sclerosis, stroke, dizziness,schizophrenia, depression, addiction, motion sickness and sleepdisorders including narcolepsy, and other diseases including asthma,allergy, allergy-induced airway responses, congestion, chronicobstructive pulmonary disease and gastro-intestinal disorders.

In a preferable aspect, the expression ‘diseases associated withmodulation of H3 receptors’ relates to obesity, metabolic syndrome(syndrome X), and other eating disorders, with obesity being especiallypreferred.

The invention therefore also relates to pharmaceutical compositionscomprising a compound as defined above and a pharmaceutically acceptablecarrier and/or adjuvant.

Further, the invention relates to compounds as defined above for use astherapeutically active substances, particularly as therapeutic activesubstances for the treatment and/or prevention of diseases which areassociated with the modulation of H3 receptors.

In another embodiment, the invention relates to a method for thetreatment and/or prevention of diseases which are associated with themodulation of H3 receptors, which method comprises administering atherapeutically active amount of a compound of formula I to a humanbeing or animal. A method for the treatment and/or prevention of obesityis preferred.

The invention further relates to the use of compounds of formula I asdefined above for the treatment and/or prevention of diseases which areassociated with the modulation of H3 receptors.

In addition, the invention relates to the use of compounds of formula Ias defined above for the preparation of medicaments for the treatmentand/or prevention of diseases which are associated with the modulationof H3 receptors. The use of compounds of formula I as defined above forthe preparation of medicaments for the treatment and/or prevention ofobesity is preferred.

Furthermore, the present invention relates to the use of a compound offormula I for the manufacture of a medicament for the treatment andprevention of obesity in a patient who is also receiving treatment witha lipase inhibitor and particularly, wherein the lipase inhibitor isorlistat.

The invention also provides for a method for the treatment or preventionof obesity and obesity related disorders which comprises administrationof a therapeutically effective amount of a compound according to formulaI in combination or association with a therapeutically effective amountof other drugs for the treatment of obesity or eating disorders so thattogether they give effective relief. Suitable other drugs include, butare not limited to, anorectic agents, lipase inhibitors, selectiveserotonin reuptake inhibitors (SSRI) and agents that stimulatemetabolism of body fat. Combinations or associations of the above agentsmay be encompassing separate, sequential or simultaneous administration.

The term “lipase inhibitor” refers to compounds which are capable ofinhibiting the action of lipases, for example gastric and pancreaticlipases. For example orlistat and lipstatin as described in U.S. Pat.No. 4,598,089 are potent inhibitor of lipases. Lipstatin is a naturalproduct of microbial origin, and orlistat is the result of ahydrogenation of lipstatin. Other lipase inhibitors include a class ofcompound commonly referred to as panclicins. Panclicins are analogues oforlistat (Mutoh et al, 1994). The term “lipase inhibitor” refers also top olymer bound lipase inhibitors for example described in InternationalPatent Application WO 99/34786 (Geltex Pharmaceuticals Inc.). Thesepolymers are characterized in that they have been substituted with oneor more groups that inhibit lipases. The term “lipase inhibitor” alsocomprises pharmaceutically acceptable salts of these compounds. The term“lipase inhibitor” preferably refers to tetrahydrolipstatin.Administration of a therapeutically effective amount of a compoundaccording to formula I in combination or association with atherapeutically effective amount of tetrahydrolipstatin is especiallypreferred.

Tetrahydrolipstatin (orlistat) is a known compound useful for thecontrol or prevention of obesity and hyperlipidemia. See, U.S. Pat. No.4,598,089, issued Jul. 1, 1986, which also discloses processes formaking orlistat and U.S. Pat. No. 6,004,996, which discloses appropriatepharmaceutical compositions. Further suitable pharmaceuticalcompositions are described for example in International PatentApplications WO 00/09122 and WO 00/09123. Additional processes for thepreparation of orlistat are disclosed in European Patent ApplicationsPublication Nos. 0 185 359, 0 189 577, 0 443 449, and 0 524 495.

Suitable anorectic agents of use in combination with a compound of thepresent invention include, but are not limited to, APD356, aminorex,amphechloral, amphetamine, axokine, benzphetamine, bupropion,chlorphentermine, clobenzorex, cloforex, clominorex, clortermine,CP945598, cyclexedrine, CYT009-GhrQb, dexfenfluramine,dextroamphetamine, diethylpropion, diphemethoxidine, N-ethylamphetamine,fenbutrazate, fenfluramine, fenisorex, fenproporex, fludorex,fluminorex, furfurylmethylamphetamine, levamfetamine, levophacetoperane,mazindol, mefenorex, metamfepramone, methamphetamine, metreleptin,norpseudoephedrine, pentorex, phendimetrazine, phenmetrazine,phentermine, phenylpropanolamine, picilorex, rimonabant, sibutramine,SLV319, SNAP 7941, SR147778 (Surinabant), steroidal plant extract (e.g.P57) and TM30338 and pharmaceutically acceptable salts thereof.

Most preferable anorectic agents are sibutramine, rimonabant andphentermine.

Suitable selective serotonin reuptake inhibitors of use in combinationwith a compound of the present invention include: fluoxetine,fluvoxamine, paroxetine and sertraline, and pharmaceutically acceptablesalts thereof.

Suitable agents that stimulate metabolism of body fat include, but arenot limited to, growth hormone agonist (e.g. AOD-9604).

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of obesity in a patient who is alsoreceiving treatment with a compound selected from the group consistingof a lipase inhibitor, an anorectic agent, a selective serotoninreuptake inhibitor, and an agent that stimulates metabolism of body fat,is also an embodiment of the present invention.

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of obesity in a patient who is alsoreceiving treatment with a lipase inhibitor, preferably withtetrahydrolipstatin, is also an embodiment of the present invention.

The invention also provides for a method of treatment or prevention ofType II diabetes (non-insulin dependent diabetes mellitus (NIDDM)) in ahuman which comprises administration of a therapeutically effectiveamount of a compound according to formula I in combination orassociation with a therapeutically effective amount of a lipaseinhibitor, particularly, wherein the lipase inhibitor istetrahydrolipstatin. Also an embodiment of the invention is the methodas described above for the simultaneous, separate or sequentialadministration of a compound according to formula I and a lipaseinhibitor, particularly tetrahydrolipstatin.

It is a further preferred embodiment to provide a method of treatment orprevention of Type II diabetes (non-insulin dependent diabetes mellitus(NIDDM)) in a human which comprises administration of a therapeuticallyeffective amount of a compound according to formula I in combination orassociation with a therapeutically effective amount of an anti-diabeticagent.

The term “anti-diabetic agent” refers to compounds selected from thegroup consisting of 1) PPARγ agonists such as pioglitazone (actos) orrosiglitazone (avandia), and the like; 2) biguanides such as metformin(glucophage), and the like; 3) sulfonylureas such as glibenclamide,glimepiride (amaryl), glipizide (glucotrol), glyburide (DiaBeta), andthe like; 4) nonsulfonylureas such as nateglinide (starlix), repaglimide(prandin), and the like; 5) PPARα/γ agonists such as GW-2331, and thelike 6) DPP-IV-inhibitors such as LAF-237 (vildagliptin), MK-0431,BMS-477118 (saxagliptin) or GSK23A and the like; 7) Glucokinaseactivators such as the compounds disclosed in e.g. WO 00/58293 A1, andthe like; 8) α-Glucosidase inhibitors such as acarbose (precose) ormiglitol (glyset), and the like.

Also an embodiment of the invention is the method as described above forthe simultaneous, separate or sequential administration of a compoundaccording to formula I and a therapeutically effective amount of ananti-diabetic agent.

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of Type II diabetes in a patient who isalso receiving treatment with an anti-diabetic agent is also anembodiment of the present invention.

It is a further preferred embodiment to provide a method of treatment orprevention of dyslipidemias in a human which comprises administration ofa therapeutically effective amount of a compound according to formula Iin combination or association with a therapeutically effective amount ofa lipid lowering agent.

The term “lipid lowering agent” refers to compounds selected from thegroup consisting of 1) bile acid sequestrants such as cholestyramine(questran), colestipol (colestid), and the like; 2) HMG-CoA reductaseinhibitors such as atorvastatin (lipitor), cerivastatin (baycol),fluvastatin (lescol), pravastatin (pravachol), simvastatin (zocor) andthe like; 3) cholesterol absorption inhibitors such as ezetimibe, andthe like; 4) CETP inhibitors such as torcetrapib, JTT 705, and the like;5) PPARα-agonists such as beclofibrate, gemfibrozil (lopid), fenofibrate(lipidil), bezafibrate (bezalip), and the like; 6) lipoprotein synthesisinhibitors such as niacin, and the like; and 7) niacin receptor agonistssuch as nicotinic acid, and the like.

Also an embodiment of the invention is the method as described above forthe simultaneous, separate or sequential administration of a compoundaccording to formula I and a therapeutically effective amount of a lipidlowering agent.

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of dyslipidemias in a patient who isalso receiving treatment with a lipid lowering agent, is also anembodiment of the present invention.

It is a further preferred embodiment to provide a method of treatment orprevention of hypertension in a human which comprises administration ofa therapeutically effective amount of a compound according to formula Iin combination or association with a therapeutically effective amount ofan anti-hypertensive agent.

The term “anti-hypertensive agent” or “blood-pressure lowering agent”refers to compounds selected from the group consisting of 1)Angiotensin-converting Enzyme (ACE) Inhibitors including benazepril(lotensin), captopril (capoten), enalapril (vasotec), fosinopril(monopril), lisinopril (prinivil, zestril), moexipril (univasc),perindopril (coversum), quinapril (accupril), ramipril (altace),trandolapril (mavik), and the like; 2) Angiotensin II ReceptorAntagonists including candesartan (atacand), eprosartan (teveten),irbesartan (avapro), losartan (cozaar), telmisartan (micadisc),valsartan (diovan), and the like; 3) Adrenergic Blockers (peripheral orcentral) such as the beta-adrenergic blockers including acebutolol(sectrol), atenolol (tenormin), betaxolol (kerlone), bisoprolol(zebeta), carteolol (cartrol), metoprolol (lopressor; toprol-XL),nadolol (corgard), penbutolol (levatol), pindolol (visken), propranolol(inderal), timolol (blockadren) and the like; alpha/beta adrenergicblockers including carvedilol (coreg), labetalol (normodyne), and thelike; alpha-1 adrenergic blockers including prazosin (minipress),doxazosin (cardura), terazosin (hytrin), phenoxybenzamine (dibenzyline),and the like; peripheral adrenergic-neuronal blockers includingguanadrel (hylorel), guanethidine (ismelin), reserpine (serpasil), andthe like; alpha-2 adrenergic blockers including a-methyldopa (aldomet),clonidine (catapres), guanabenz (wytensin), guanfacine (tenex), and thelike; 4) Blood Vessel Dilators (Vasodilators) including hydralazine(apresoline), minoxidil (lonitren), clonidine (catapres), and the like;5) Calcium Channel Blockers including amlodipine (norvasc), felodipine(plendil), isradipine (dynacirc), nicardipine (cardine sr), nifedipine(procardia, adalat), nisoldipine (sular), diltiazem (cardizem),verapamil (isoptil), and the like; 6) Diuretics such as thiazides andthiazides-like agents, including hydrochlorothiazide (hydrodiuril,microzide), chlorothiazide (diuril), chlorthalidone (hygroton),indapamide (lozol), metolazone (mykrox), and the like; loop diuretics,such as bumetanide (bumex) and furosemide (lasix), ethacrynic acid(edecrin), torsemide (demadex), and the like; potassium-sparingdiuretics including amiloride (midamor), triamterene (dyrenium),spironolactone (aldactone), and the tiamenidine (symcor) and the like;7) Tyrosine Hydroxylase Inhibitors, including metyrosine (demser), andthe like; 8) Neutral Endopeptidase Inhibitors, including BMS-186716(omapatrilat), UK-79300 (candoxatril), ecadotril (sinorphan), BP-1137(fasidotril), UK-79300 (sampatrilat) and the like; and 9) EndothelinAntagonists including tezosentan, A308165, and the like.

Also an embodiment of the invention is the method as described above forthe simultaneous, separate or sequential administration of a compoundaccording to formula I and a therapeutically effective amount of aanti-hypertensive agent.

The use of a compound of formula I in the manufacture of a medicamentfor the treatment and prevention of hypertension in a patient who isalso receiving treatment with an anti-hypertensive agent, is also anembodiment of the present invention.

The compounds of formula I and their pharmaceutically acceptable saltspossess valuable pharmacological properties. Specifically, it has beenfound that the compounds of the present invention are good histamine 3receptor (H3R) antagonists and/or inverse agonists.

The following test was carried out in order to determine the activity ofthe compounds of formula (I).

Binding Assay with ³H-(R)α-methylhistamine

Saturation binding experiments were performed using HR3-CHO membranesprepared as described in Takahashi, K, Tokita, S., Kotani, H. (2003) J.Pharmacol. Exp. Therapeutics 307, 213-218.

An appropriate amount of membrane (60 to 80 μg protein/well) wasincubated with increasing concentrations of ³H(R)α-Methylhistaminedi-hydrochloride (0.10 to 10 nM). Non specific binding was determinedusing a 200 fold excess of cold (R)α-Methylhistamine dihydrobromide (500nM final concentration). The incubation was carried out at roomtemperature (in deep-well plates shaking for three hours). The finalvolume in each well was 250 μl. The incubation was followed by rapidfiltration on GF/B filters (pre-soaked with 100 μl of 0.5% PEI in Tris50 mM shaking at 200 rpm for two hours). The filtration was made using acell-harvester and the filter plates were then washed five times withice cold washing buffer containing 0.5 M NaCl. After harvesting, theplates were dried at 55° C. for 60 min, then we added scintillationfluid (Microscint 40, 40 microl in each well) and the amount ofradioactivity on the filter was determined in Packard top-counter aftershaking the plates for two hours at 200 rpm at room temperature.

Binding Buffer: 50 mM Tris-HCl pH 7.4 and 5 mM MgCl₂×6H₂O pH 7.4.Washing Buffer: 50 mM Tris-HCl pH 7.4 and 5 mM MgCl₂×6H₂O and 0.5 M NaClpH 7.4.

Indirect measurement of affinity of H3R inverse agonists: twelveincreasing concentrations (ranging from 10 μM to 0.3 nM) of the selectedcompounds were always tested in competition binding experiments usingmembrane of the human HR3-CHO cell line. An appropriate amount ofprotein, e.g. approximately 500 cpm binding of RAMH at Kd, wereincubated for 1 hour at room temperature in 250 μl final volume in96-well plates in presence of ³H(R)(α-Methylhistamine (1 nM finalconcentration=Kd). Non-specific binding was determined using a 200 foldexcess of cold (R)α-Methylhistamine dihydrobromide.

All compounds were tested at a single concentration in duplicates.Compounds that showed an inhibition of [³H]-RAMH by more than 50% weretested again to determine IC₅₀ in a serial dilution experiment. Ki'swere calculated from IC₅₀ based on Cheng-Prusoff equation (Cheng, Y,Prusoff, W H (1973) Biochem Pharmacol 22, 3099-3108).

The compounds of the present invention exhibit K_(i) values within therange of about 1 nM to about 1000 nM, preferably of about 1 nM to about100 nM, and more preferably of about 1 nM to about 30 nM. The followingtable shows measured values for some selected compounds of the presentinvention.

K_(i) (nM) Example 9 28 Example 52 123 Example 68 156

The compounds of formula (I) and their pharmaceutically acceptable saltsand esters can be used as medicaments, e.g. in the form ofpharmaceutical preparations for enteral, parenteral or topicaladministration. They can be administered, for example, perorally, e.g.in the form of tablets, coated tablets, dragées, hard and soft gelatinecapsules, solutions, emulsions or suspensions, rectally, e.g. in theform of suppositories, parenterally, e.g. in the form of injectionsolutions or infusion solutions, or topically, e.g. in the form ofointments, creams or oils.

The production of the pharmaceutical preparations can be effected in amanner which will be familiar to any person skilled in the art bybringing the described compounds of formula (I) and theirpharmaceutically acceptable, into a galenical administration formtogether with suitable, non-toxic, inert, therapeutically compatiblesolid or liquid carrier materials and, if desired, usual pharmaceuticaladjuvants.

Suitable carrier materials are not only inorganic carrier materials, butalso organic carrier materials. Thus, for example, lactose, corn starchor derivatives thereof, talc, stearic acid or its salts can be used ascarrier materials for tablets, coated tablets, dragées and hard gelatinecapsules. Suitable carrier materials for soft gelatine capsules are, forexample, vegetable oils, waxes, fats and semi-solid and liquid polyols(depending on the nature of the active ingredient no carriers are,however, required in the case of soft gelatine capsules). Suitablecarrier materials for the production of solutions and syrups are, forexample, water, polyols, sucrose, invert sugar and the like. Suitablecarrier materials for injection solutions are, for example, water,alcohols, polyols, glycerol and vegetable oils. Suitable carriermaterials for suppositories are, for example, natural or hardened oils,waxes, fats and semi-liquid or liquid polyols. Suitable carriermaterials for topical preparations are glycerides, semi-synthetic andsynthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins,liquid fatty alcohols, sterols, polyethylene glycols and cellulosederivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents,consistency-improving agents, flavor-improving agents, salts for varyingthe osmotic pressure, buffer substances, solubilizers, colorants andmasking agents and antioxidants come into consideration aspharmaceutical adjuvants.

The dosage of the compounds of formula (I) can vary within wide limitsdepending on the disease to be controlled, the age and the individualcondition of the patient and the mode of administration, and will, ofcourse, be fitted to the individual requirements in each particularcase. For adult patients a daily dosage of about 1 mg to about 1000 mg,especially about 1 mg to about 100 mg, comes into consideration.Depending on the dosage it is convenient to administer the daily dosagein several dosage units.

The pharmaceutical preparations conveniently contain about 0.1-500 mg,preferably 0.5-100 mg, of a compound of formula (I).

The following examples serve to illustrate the present invention in moredetail. They are, however, not intended to limit its scope in anymanner.

EXAMPLES Example 1 Isopropyl-4-(4-phenyl-thiazol-2-yl)-piperidine Step1: 4-(4-Phenyl-thiazol-2-yl)-piperidine hydrobromide (Intermediate 1)

A mixture of 1 g (4.1 mmol) 4-thiocarbamoyl-piperidine-1-carboxylic acidtert-butyl ester (commercially available) and 0.816 g (4.1 mmol)2-bromo-1-phenyl-ethanone (commercially available) in 10 ml methanol wasstirred at 70° C. for 22 h. After evaporation to dryness the residue wassuspended in diethyl ether and filtered. The residue washed with diethylether and dried under vacuum to yield 1.279 g (96%) of the titlecompound in white crystalline form. (m/e): 245.2 (MH⁺(−HBr); 100%).

Step 2: 1-Isopropyl-4-(4-phenyl-thiazol-2-yl)-piperidine

A mixture of 24.5 mg (0.1 mmol) 4-(4-phenyl-thiazol-2-yl)-piperidinehydrobromide, excess acetone and excess sodium triacetoxyborohydride in1 ml THF and 20 μl acetic acid was stirred at room temperature for 16 h.After addition of 0.2 ml water, 0.2 ml methanol and 0.15 ml NEt₃ themixture was purified by preparative HPLC on reversed phase eluting witha gradient of acetonitrile/water (0.1% NEt₃) to yield after evaporationof the product fractions 12.8 mg (45 %) of the title compound. (m/e):287.3 (MH⁺; 100%).

According to the procedure described in step 1 for the synthesis ofintermediate 1 the further intermediates 2 to 33 were prepared fromdifferent starting materials as given in Table 1.

TABLE 1 MH+ (-HBr) found Intermediate Name Starting materials MW [100%]2 4-[4-(3,4-difluoro- 4-thiocarbamoyl-piperidine-1- 361.25 281.1phenyl)-thiazol-2-yl]- carboxylic acid tert-butyl ester piperidine;(commercially available) and hydrobromide 2-bromo-1-(3,4-difluoro-phenyl)-ethanone (commercially available) 3 4-(4-cyclohexyl-4-thiocarbamoyl-piperidine-1- 331.32 251.2 thiazol-2-yl)- carboxylicacid tert-butyl ester piperidine; (commercially available) andhydrobromide 2-bromo-1-cyclohexyl-ethanone (Tetrahedron 26, 5611, 1970)4 4-[4-(4-methoxy- 4-thiocarbamoyl-piperidine-1- 355.30 275.2phenyl)-thiazol-2-yl]- carboxylic acid tert-butyl ester piperidine;(commercially available) and hydrobromide 2-bromo-1-(4-methoxy-phenyl)-ethanone (commercially available) 5 4-[4-(2-fluoro-4-4-thiocarbamoyl-piperidine-1- 292.38 293.2 methoxy-phenyl)- carboxylicacid tert-butyl ester thiazol-2-yl]- (commercially available) andpiperidine; 2-bromo-1-(2-fluoro-4- hydrobromide methoxy-phenyl)-ethanone(commercially available) 6 4-[4-(2-methoxy-4-thiocarbamoyl-piperidine-1- 355.30 275.2 phenyl)-thiazol-2-yl]-carboxylic acid tert-butyl ester piperidine; (commercially available)and hydrobromide 2-bromo-1-(2-methoxy- phenyl)-ethanone (commerciallyavailable) 7 2-methyl-3-(2- 4-thiocarbamoyl-piperidine-1- 341.27 261.1piperidin-4-yl-thiazol- carboxylic acid tert-butyl ester 4-yl)-pyrazine;(commercially available) and hydrobromide 2-bromo-1-(3-methyl-pyrazin-2-yl)-ethanone (WO 2004/014884) 8 4-[4-(2- 4-thiocarbamoyl-piperidine-1-393.27 313 trifluoromethyl- carboxylic acid tert-butyl esterphenyl)-thiazol-2-yl]- (commercially available) and piperidine;2-bromo-1-(2-trifluoromethyl- hydrobromide phenyl)-ethanone(commercially available) 9 4-[4-(4-chloro- 4-thiocarbamoyl-piperidine-1-359.72 279.1 phenyl)-thiazol-2-yl]- carboxylic acid tert-butyl esterpiperidine; (commercially available) and hydrobromide2-bromo-1-(4-chloro-phenyl)- ethanone (commercially available) 104-[4-(3-fluoro- 4-thiocarbamoyl-piperidine-1- 343.26 263phenyl)-thiazol-2-yl]- carboxylic acid tert-butyl ester piperidine;(commercially available) and hydrobromide 2-bromo-1-(3-fluoro-phenyl)-ethanone (commercially available) 11 4-(5-methyl-4-phenyl-4-thiocarbamoyl-piperidine-1- 339.30 259.1 thiazol-2-yl)- carboxylicacid tert-butyl ester piperidine; (commercially available) andhydrobromide 2-bromo-1-phenyl-propan-1- one (commercially available) 124-[4-(2-fluoro-3- 4-thiocarbamoyl-piperidine-1- 411.26 331trifluoromethyl- carboxylic acid tert-butyl ester phenyl)-thiazol-2-yl]-(commercially available) and piperidine; 2-bromo-1-(2-fluoro-3-hydrobromide trifluoromethyl-phenyl)- ethanone (commercially available)13 4-(2-piperidin-4-yl- 4-thiocarbamoyl-piperidine-1- 350.29 270thiazol-4-yl)- carboxylic acid tert-butyl ester benzonitrile;(commercially available) and hydrobromide4-(2-bromo-acetyl)-benzonitrile (commercially available) 14 4-[4-(4-4-thiocarbamoyl-piperidine-1- 393.27 313.1 trifluoromethyl- carboxylicacid tert-butyl ester phenyl)-thiazol-2-yl]- (commercially available)and piperidine; 2-bromo-1-(4-trifluoromethyl- hydrobromidephenyl)-ethanone (commercially available) 15 4-[4-(5,5,8,8-4-thiocarbamoyl-piperidine-1- 435.48 355.1 tetramethyl-5,6,7,8-carboxylic acid tert-butyl ester tetrahydro- (commercially available)and naphthalen-2-yl)- 2-bromo-1-(5,5,8,8- thiazol-2-yl]-tetramethyl-5,6,7,8-tetrahydro- piperidine; naphthalen-2-yl)-ethanonehydrobromide (commercially available) 16 4-[4-(3-methoxy-4-thiocarbamoyl-piperidine-1- 355.3 275 phenyl)-thiazol-2-yl]-carboxylic acid tert-butyl ester piperidine; (commercially available)and hydrobromide 2-bromo-1-(3-methoxy- phenyl)-ethanone (commerciallyavailable) 17 4-(4-p-tolyl-thiazol-2- 4-thiocarbamoyl-piperidine-1-339.3 258.9 yl)-piperidine; carboxylic acid tert-butyl esterhydrobromide (commercially available) and 2-bromo-1-(4-methyl-phenyl)-ethanone (commercially available) 18 4-[4-(4-4-thiocarbamoyl-piperidine-1- 391.28 311 difluoromethoxy- carboxylicacid tert-butyl ester phenyl)-thiazol-2-yl]- (commercially available)and piperidine; 2-bromo-1-(4- hydrobromide difluoromethoxy-phenyl)-ethanone (commercially available) 19 4-[4-(2,3-dihydro-4-thiocarbamoyl-piperidine-1- 383.31 303.1 benzo[1,4]dioxin-6-carboxylic acid tert-butyl ester yl)-thiazol-2-yl]- (commerciallyavailable) and piperidine; 2-bromo-1-(2,3-dihydro- hydrobromidebenzo[1,4]dioxin-6-yl)- ethanone (commercially available) 204-[4-(3,4-dihydro-2H- 4-thiocarbamoyl-piperidine-1- 397.34 317benzo[b][1,4]dioxepin- carboxylic acid tert-butyl ester7-yl)-thiazol-2-yl] (commercially available) and piperidine;2-bromo-1-(3,4-dihydro-2H- hydrobromide benzo[b][1,4]dioxepin-7-yl)-ethanone (commercially available) 21 3-(2-piperidin-4-yl-4-thiocarbamoyl-piperidine-1- 350.29 270.1 thiazol-4-yl)- carboxylicacid tert-butyl ester benzonitrile; (commercially available) andhydrobromide 3-(2-bromo-acetyl)-benzonitrile (commercially available) 224-[4-(4-pyrrolidin-1- 4-thiocarbamoyl-piperidine-1- 394.38 313.7yl-phenyl)-thiazol-2- carboxylic acid tert-butyl ester yl]-piperidine;(commercially available) and hydrobromide 2-bromo-1-(4-pyrrolidin-1-yl-phenyl)-ethanone (commercially available) 23 4-[4-(4-4-thiocarbamoyl-piperidine-1- 409.27 329.4 trifluoromethoxy- carboxylicacid tert-butyl ester phenyl)-thiazol-2-yl]- (commercially available)and piperidine; 2-bromo-1-(4- hydrobromide trifluoromethoxy-phenyl)-ethanone (commercially available) 24 4-[4-(3-4-thiocarbamoyl-piperidine-1- 393.27 313.1 trifluoromethyl- carboxylicacid tert-butyl ester phenyl)-thiazol-2-yl]- (commercially available)and piperidine; 2-bromo-1-(3-trifluoromethyl- hydrobromidephenyl)-ethanone (commercially available) 25 4-[4-(3,4-dimethoxy-4-thiocarbamoyl-piperidine-1- 385.33 305.3 phenyl)-thiazol-2-yl]-carboxylic acid tert-butyl ester piperidine; (commercially available)and hydrobromide 2-bromo-1-(3,4-dimethoxy- phenyl)-ethanone(commercially available) 26 4-(4-benzo[1,3]dioxol-4-thiocarbamoyl-piperidine-1- 369.29 288.8 5-yl-thiazol-2-yl)-carboxylic acid tert-butyl ester piperidine; (commercially available)and hydrobromide 1-benzo[1,3]dioxol-5-yl-2- bromo-ethanone (commerciallyavailable) 27 4-[4-(4-bromo- 4-thiocarbamoyl-piperidine-1- 418.2 339phenyl)-5-methyl- carboxylic acid tert-butyl ester thiazol-2-yl]-(commercially available) and piperidine; 2-bromo-1-(4-bromo-phenyl)-hydrobromide propan-1-one (commercially available) 284-(2-piperidin-4-yl- 4-thiocarbamoyl-piperidine-1- 407.18 246.1thiazol-4-yl)-pyridine; carboxylic acid tert-butyl ester dihydrobromide(commercially available) and 2-bromo-1-pyridin-4-yl- ethanone(commercially available) 29 4-(4-thiophen-3-yl-4-thiocarbamoyl-piperidine-1- 331.3 250.9 thiazol-2-yl)- carboxylic acidtert-butyl ester piperidine; (commercially available) and hydrobromide2-bromo-1-thiophen-3-yl- ethanone (commercially available) 304-(4-thiophen-2-yl- 4-thiocarbamoyl-piperidine-1- 331.3 250.9thiazol-2-yl)- carboxylic acid tert-butyl ester piperidine;(commercially available) and hydrobromide 2-bromo-1-thiophen-2-yl-ethanone (commercially available) 31 4-[4-(3,4-dichloro-4-thiocarbamoyl-piperidine-1- 394.17 315 phenyl)-thiazol-2-yl]-carboxylic acid tert-butyl ester piperidine; (commercially available)and hydrobromide 2-bromo-1-(3,4-dichloro- phenyl)-ethanone (commerciallyavailable) 32 4-[4-(2,4-dimethoxy- 4-thiocarbamoyl-piperidine-1- 385.33305.1 phenyl)-thiazol-2-yl]- carboxylic acid tert-butyl esterpiperidine; (commercially available) and hydrobromide2-bromo-1-(2,4-dimethoxy- phenyl)-ethanone (commercially available) 334-[4-(3,5-bis- 4-thiocarbamoyl-piperidine-1- 461.27 381.1trifluoromethyl- carboxylic acid tert-butyl ester phenyl)-thiazol-2-yl]-(commercially available) and piperidine; 2-bromo-1-(3,5-bis-hydrobromide trifluoromethyl-phenyl)- ethanone (commercially available)

According to the procedure described for the synthesis of Example 1further thiazole derivatives have been synthesized from the respectiveintermediate listed in Table 1 and the respective aldehyde or ketonementioned in Table 2. In cases where the thiazole intermediates werereacted with ketones the reaction temperature was shifted from roomtemperature (used in the cases where thiazole intermediates were reactedwith aldehydes) to 40° C. The examples are compiled in Table 2 andcomprise Example 2 to Example 64.

TABLE 2 MH⁺ Example found No. Name Starting Materials MW (100%) 21-cyclopentyl-4-(4-phenyl- 4-(4-phenyl-thiazol-2-yl)- 312.5 312.2thiazol-2-yl)-piperidine piperidine; hydrobromide (Intermediate 1) andcyclopentanone (commercially available) 3 4-[4-(3,4-difluoro-phenyl)-4-[4-(3,4-difluoro-phenyl)- 336.4 337.3 thiazol-2-yl]-1-isobutyl-thiazol-2-yl-piperidine; piperidine hydrobromide (Intermediate 2) and2-methyl-propionaldehyde (commercially available) 44-[4-(3,4-difluoro-phenyl)- 4-[4-(3,4-difluoro-phenyl)- 322.4 323.2thiazol-2-yl]-1-isopropyl- thiazol-2-yl]-piperidine; piperidinehydrobromide (Intermediate 2) and acetone (commercially available) 51-cyclopentyl-4-[4-(3,4- 4-[4-(3,4-difluoro-phenyl)- 348.5 349.2difluoro-phenyl)-thiazol-2- thiazol-2-yl]-piperidine; yl]-piperidinehydrobromide (Intermediate 2) and cyclopentanone (commerciallyavailable) 6 4-(4-cyclohexyl-thiazol-2- 4-(4-cyclohexyl-thiazol-2-yl)-306.5 307.3 yl)-1-isobutyl-piperidine piperidine; hydrobromide(Intermediate 3) and 2-methyl-propionaldehyde (commercially available) 74-(4-cyclohexyl-thiazol-2- 4-(4-cyclohexyl-thiazol-2-yl)- 318.5 319.1yl)-1-cyclopentyl- piperidine; hydrobromide piperidine (Intermediate 3)and cyclopentanone (commercially available) 8 1-isobutyl-4-[4-(4-4-[4-(4-methoxy-phenyl)- 330.5 331.2 methoxy-phenyl)-thiazol-thiazol-2-yl]-piperidine; 2-yl]-piperidine hydrobromide (Intermediate 4)and 2-methyl-propionaldehyde (commercially available) 91-isopropyl-4-[4-(4- 4-[4-(4-methoxy-phenyl)- 316.5 317.2methoxy-phenyl)-thiazol- thiazol-2-yl]-piperidine; 2-yl]-piperidinehydrobromide (Intermediate 4) and acetone (commercially available) 101-cyclopentyl-4-[4-(4- 4-[4-(4-methoxy-phenyl)- 342.5 343.2methoxy-phenyl)-thiazol- thiazol-2-yl]-piperidine; 2-yl]-piperidinehydrobromide (Intermediate 4) and cyclopentanone (commerciallyavailable) 11 4-[4-(2-fluoro-4-methoxy- 4-[4-(2-fluoro-4-methoxy- 348.5349.3 phenyl)-thiazol-2-yl]-1- phenyl)-thiazol-2-yl]-isobutyl-piperidine piperidine; hydrobromide (Intermediate 5) and2-methyl-propionaldehyde (commercially available) 124-[4-(2-fluoro-4-methoxy- 4-[4-(2-fluoro-4-methoxy- 334.5 335.3phenyl)-thiazol-2-yl]-1- phenyl)-thiazol-2-yl]- isopropyl-piperidinepiperidine; hydrobromide (Intermediate 5) and acetone (commerciallyavailable) 13 1-cyclopentyl-4-[4-(2- 4-[4-(2-fluoro-4-methoxy- 360.5361.2 fluoro-4-methoxy-phenyl)- phenyl)-thiazol-2-yl]-thiazol-2-yl]-piperidine piperidine; hydrobromide (Intermediate 5) andcyclopentanone (commercially available) 14 1-isobutyl-4-[4-(2-4-[4-(2-methoxy-phenyl)- 330.5 331.2 methoxy-phenyl)-thiazol-thiazol-2-yl]-piperidine; 2-yl]-piperidine hydrobromide (Intermediate 6)and 2-methyl-propionaldehyde (commercially available) 151-isopropyl-4-[4-(2- 4-[4-(2-methoxy-phenyl)- 316.5 317.2methoxy-phenyl)-thiazol- thiazol-2-yl]-piperidine; 2-yl]-piperidinehydrobromide (Intermediate 6) and acetone (commercially available) 161-cyclopentyl-4-[4-(2- 4-[4-(2-methoxy-phenyl)- 342.5 343.2methoxy-phenyl)-thiazol- thiazol-2-yl]-piperidine; 2-yl]-piperidinehydrobromide (Intermediate 6) and cyclopentanone (commerciallyavailable) 17 2-[2-(1-isobutyl-piperidin- methyl-3-(2-piperidin-4-yl-316.5 317.2 4-yl)-thiazol-4-yl]-3- thiazol-4-yl)-pyrazine;methyl-pyrazine hydrobromide (Intermediate 7) and2-methyl-propionaldehyde (commercially available) 182-[2-(1-cyclopentyl- methyl-3-(2-piperidin-4-yl- 328.5 329.3piperidin-4-yl)-thiazol-4- thiazol-4-yl)-pyrazine; yl]-3-methyl-pyrazinehydrobromide (Intermediate 7) and cyclopentanone (commerciallyavailable) 19 1-isobutyl-4-[4-(2- 4-[4-(2-trifluoromethyl- 368.5 369.1trifluoromethyl-phenyl)- phenyl)-thiazol-2-yl]- thiazol-2-yl]-piperidinepiperidine; hydrobromide (Intermediate 8) and 2-methyl-propionaldehyde(commercially available) 20 1-cyclopentyl-4-[4-(2-4-[4-(2-trifluoromethyl- 380.5 381.3 trifluoromethyl-phenyl)-phenyl)-thiazol-2-yl]- thiazol-2-yl]-piperidine piperidine; hydrobromide(Intermediate 8) and cyclopentanone (commercially available) 214-[4-(4-chloro-phenyl)- 4-[4-(4-chloro-phenyl)- 334.9 335.3thiazol-2-yl]-1-isobutyl- thiazol-2-yl]-piperidine; piperidinehydrobromide (Intermediate 9) and 2-methyl-propionaldehyde (commerciallyavailable) 22 4-[4-(4-chloro-phenyl)- 4-[4-(4-chloro-phenyl)- 320.9321.1 thiazol-2-yl]-1-isopropyl- thiazol-2-yl]-piperidine; piperidinehydrobromide (Intermediate 9) and acetone (commercially available) 234-[4-(4-chloro-phenyl)- 4-[4-(4-chloro-phenyl)- 346.9 347.1thiazol-2-yl]-1-cyclopentyl- thiazol-2-yl]-piperidine; piperidinehydrobromide and cyclopentanone (commercially available) 244-[4-(3-fluoro-phenyl)- 4-[4-(3-fluoro-phenyl)- 318.5 319.2thiazol-2-yl]-1-isobutyl- thiazol-2-yl]-piperidine; piperidinehydrobromide (Intermediate 10) and 2-methyl-propionaldehyde(commercially available) 25 4-[4-(3-fluoro-phenyl)-4-[4-(3-fluoro-phenyl)- 304.4 305.2 thiazol-2-yl]-1-isopropyl-thiazol-2-yl]-piperidine; piperidine hydrobromide (Intermediate 10) andacetone (commercially available) 26 1-cyclopentyl-4-[4-(3-4-[4-(3-fluoro-phenyl)- 330.5 331.2 fluoro-phenyl)-thiazol-2-thiazol-2-yl]-piperidine; yl]-piperidine hydrobromide (Intermediate 10)and cyclopentanone (commercially available) 271-cyclopentyl-4-(5-methyl- 4-(5-methyl-4-phenyl-thiazol- 326.5 327.24-phenyl-thiazol-2-yl)- 2-yl)-piperidine; piperidine hydrobromide(Intermediate 11) and cyclopentanone (commercially available) 284-[4-(2-fluoro-3- 4-[4-(2-fluoro-3- 372.4 373.1 trifluoromethyl-phenyl)-trifluoromethyl-phenyl)- thiazol-2-yl]-1-isopropyl-thiazol-2-yl]-piperidine; piperidine hydrobromide (Intermediate 12) andacetone (commercially available) 29 4-[2-(1-isopropyl-4-(2-piperidin-4-yl-thiazol-4- 311.5 312.3 piperidin-4-yl)-thiazol-4-yl)-benzonitrile; hydrobromide yl]-benzonitrile (Intermediate 13) andacetone (commercially available) 30 1-isopropyl-4-[4-(4-4-[4-(4-trifluoromethyl- 354.4 355.3 trifluoromethyl-phenyl)-phenyl)-thiazol-2-yl]- thiazol-2-yl]-piperidine piperidine; hydrobromide(Intermediate 14) and acetone (commercially available) 311-isopropyl-4-[4-(3- 4-[4-(3-methoxy-phenyl)- 316.5 317.2methoxy-phenyl)-thiazol- thiazol-2-yl]-piperidine; 2-yl]-piperidinehydrobromide (Intermediate 16) and acetone (commercially available) 321-isopropyl-4-(4-p-tolyl- 4-(4-p-tolyl-thiazol-2-yl)- 300.5 301.3thiazol-2-yl)-piperidine piperidine; hydrobromide (Intermediate 17) andacetone (commercially available) 33 4-[4-(4-difluoromethoxy-4-[4-(4-difluoromethoxy- 352.4 353.2 phenyl)-thiazol-2-yl]-1-phenyl)-thiazol-2-yl]- isopropyl-piperidine piperidine; hydrobromide(Intermediate 18) and acetone (commercially available) 344-[4-(2,3-dihydro- 4-[4-(2,3-dihydro- 344.5 345.2benzo[1,4]dioxin-6-yl)- benzo[1,4]dioxin-6-yl)-thiazol-thiazol-2-yl]-1-isopropyl- 2-yl]-piperidine (Intermediate piperidine19); hydrobromide and acetone (commercially available) 354-[4-(3,4-dihydro-2H- 4-[4-(3,4-dihydro-2H- 358.5 359.2benzo[b][1,4]dioxepin-7- benzo[b][1,4]dioxepin-7-yl)-yl)-thiazol-2-yl]-1- thiazol-2-yl]-piperidine; isopropyl-piperidinehydrobromide (Intermediate 20) and acetone (commercially available) 363-[2-(1-isopropyl- 3-(2-piperidin-4-yl-thiazol-4- 311.5 312.3piperidin-4-yl)-thiazol-4- yl)-benzonitrile; hydrobromideyl]-benzonitrile (Intermediate 21) and acetone (commercially available)37 1-isopropyl-4-[4-(4- 4-[4-(4-pyrrolidin-1-yl- 355.5 356.4pyrrolidin-1-yl-phenyl)- phenyl)-thiazol-2-yl]- thiazol-2-yl]-piperidinepiperidine; hydrobromide (Intermediate 22) and acetone (commerciallyavailable) 38 1-isopropyl-4-[4-(4- 4-[4-(4-trifluoromethoxy- 370.4 371.2trifluoromethoxy-phenyl)- phenyl)-thiazol-2-yl]-thiazol-2-yl]-piperidine piperidine; hydrobromide (Intermediate 23) andacetone (commercially available) 39 1-isopropyl-4-[4-(3-4-[4-(3-trifluoromethyl- 354.4 355.3 trifluoromethyl-phenyl)-phenyl)-thiazol-2-yl]- thiazol-2-yl]-piperidine piperidine; hydrobromide(Intermediate 24) and acetone (commercially available) 404-[4-(3,4-dimethoxy- 4-[4-(3,4-dimethoxy-phenyl)- 346.5 347.2phenyl)-thiazol-2-yl]-1- thiazol-2-yl]-piperidine; isopropyl-piperidinehydrobromide (Intermediate 25) and acetone (commercially available) 414-(4-benzo[1,3]dioxol-5- 4-(4-benzo[1,3]dioxol-5-yl- 330.5 331.2yl-thiazol-2-yl)-1- thiazol-2-yl)-piperidine; isopropyl-piperidinehydrobromide (Intermediate 26) and acetone (commercially available) 424-[4-(4-bromo-phenyl)-5- 4-[4-(4-bromo-phenyl)-5- 379.4 379.2methyl-thiazol-2-yl]-1- methyl-thiazol-2-yl]- isopropyl-piperidinepiperidine; hydrobromide (Intermediate 27) and acetone (commerciallyavailable) 43 1-isopropyl-4-(4-thiophen- 4-(4-thiophen-3-yl-thiazol-2-292.5 293.2 3-yl-thiazol-2-yl)- yl)-piperidine; hydrobromide piperidine(Intermediate 29) and acetone (commercially available) 441-isopropyl-4-(4-thiophen- 4-(4-thiophen-2-yl-thiazol-2- 292.5 293.22-yl-thiazol-2-yl)- yl)-piperidine; hydrobromide piperidine(Intermediate 30) and acetone (commercially available) 454-[4-(3,4-dichloro- 4-[4-(3,4-dichloro-phenyl)- 355.3 355.2phenyl)-thiazol-2-yl]-1- thiazol-2-yl]-piperidine; isopropyl-piperidinehydrobromide (Intermediate 31) and acetone (commercially available) 464-[4-(2,4-dimethoxy- 4-[4-(2,4-dimethoxy-phenyl)- 346.5 347.1phenyl)-thiazol-2-yl]-1- thiazol-2-yl]-piperidine; isopropyl-piperidinehydrobromide (Intermediate 32) and acetone (commercially available) 474-[2-(1-cyclopentyl- 4-(2-piperidin-4-yl-thiazol-4- 337.5 338.3piperidin-4-yl)-thiazol-4- yl)-benzonitrile; hydrobromideyl]-benzonitrile (Intermediate 13) and cyclopentanone (commerciallyavailable) 48 1-cyclopentyl-4-[4-(4- 4-[4-(4-trifluoromethyl- 380.5381.3 trifluoromethyl-phenyl)- phenyl)-thiazol-2-yl]-thiazol-2-yl]-piperidine piperidine; hydrobromide (Intermediate 14) andcyclopentanone (commercially available) 49 1-cyclopentyl-4-[4-4-[4-(5,5,8,8-tetramethyl- 422.7 423.3 (5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen- 5,6,7,8-tetrahydro-2-yl)-thiazol-2-yl]-piperidine; naphthalen-2-yl)-thiazol-2- hydrobromide(Intermediate yl]-piperidine 15) and cyclopentanone (commerciallyavailable) 50 1-cyclopentyl-4-[4-(3- 4-[4-(3-methoxy-phenyl)- 342.5343.1 methoxy-phenyl)-thiazol- thiazol-2-yl]-piperidine;2-yl]-piperidine hydrobromide (Intermediate 16) and cyclopentanone(commercially available) 51 1-cyclopentyl-4-[4-(4-4-[4-(4-difluoromethoxy- 378.5 379.3 difluoromethoxy-phenyl)-phenyl)-thiazol-2-yl]- thiazol-2-yl]-piperidine piperidine; hydrobromide(Intermediate 18) and cyclopentanone (commercially available) 521-cyclopentyl-4-[4-(2,3- 4-[4-(2,3-dihydro-benzo[1,4] 370.5 371.1dihydro-benzo[1,4]dioxin- dioxin-6-yl)-thiazol-2-yl]-6-yl)-thiazol-2-yl]- piperidine; hydrobromide piperidine (Intermediate19) and cyclopentanone (commercially available) 531-cyclopentyl-4-[4-(3,4- 4-[4-(3,4-dihydro-2H- 384.5 385.2 dihydro-2H-benzo[b][1,4]dioxepin-7-yl)- benzo[b][1,4]dioxepin-7-thiazol-2-yl]-piperidine; yl)-thiazol-2-yl]-piperidine hydrobromide(Intermediate 20) and cyclopentanone (commercially available) 543-[2-(1-cyclopentyl- 3-(2-piperidin-4-yl-thiazol-4- 337.5 338.3piperidin-4-yl)-thiazol-4 yl)-benzonitrile; hydrobromideyl]-benzonitrile (Intermediate 21) and cyclopentanone (commerciallyavailable) 55 1-cyclopentyl-4-[4-(4- 4-[4-(4-trifluoromethoxy- 396.5397.3 trifluoromethoxy-phenyl)- phenyl)-thiazol-2-yl]-thiazol-2-yl]-piperidine piperidine; hydrobromide (Intermediate 23) andcyclopentanone (commercially available) 56 1-cyclopentyl-4-[4-(3-4-[4-(3-trifluoromethyl- 380.5 381.3 trifluoromethyl-phenyl)-phenyl)-thiazol-2-yl]- thiazol-2-yl]-piperidine piperidine; hydrobromide(Intermediate 24) and cyclopentanone (commercially available) 571-cyclopentyl-4-[4-(3,4- 4-[4-(3,4-dimethoxy-phenyl)- 372.5 373.1dimethoxy-phenyl)- thiazol-2-yl]-piperidine; thiazol-2-yl]-piperidinehydrobromide (Intermediate 25) and cyclopentanone (commerciallyavailable) 58 4-(4-benzo[1,3]dioxol-5- 4-(4-benzo[1,3]dioxol-5-yl- 356.5357.2 yl-thiazol-2-yl)-1- thiazol-2-yl)-piperidine;cyclopentyl-piperidine hydrobromide (Intermediate 26) and cyclopentanone(commercially available) 59 4-[4-(4-bromo-phenyl)-5-4-[4-(4-bromo-phenyl)-5- 405.4 405.3 methyl-thiazol-2-yl]-1-methyl-thiazol-2-yl]- cyclopentyl-piperidine piperidine; hydrobromide(Intermediate 27) and cyclopentanone (commercially available) 604-[2-(1-cyclopentyl- 4-(2-piperidin-4-yl-thiazol-4- 313.5 314.2piperidin-4-yl)-thiazol-4 yl)-pyridine; dihydrobromide yl]-pyridine(Intermediate 28) and cyclopentanone (commercially available) 611-cyclopentyl-4-(4- 4-(4-thiophen-3-yl-thiazol-2- 318.5 319.2thiophen-3-yl-thiazol-2- yl)-piperidine; hydrobromide yl)-piperidine(Intermediate 29) and cyclopentanone (commercially available) 621-cyclopentyl-4-[4-(3,4- 4-[4-(3,4-dichloro-phenyl)- 381.4 381dichloro-phenyl)-thiazol- thiazol-2-yl]-piperidine; 2-yl]-piperidinehydrobromide (Intermediate 31) and cyclopentanone (commerciallyavailable) 63 1-cyclopentyl-4-[4-(2,4- 4-[4-(2,4-dimethoxy-phenyl)-372.5 373.1 dimethoxy-phenyl)- thiazol-2-yl]-piperidine;thiazol-2-yl]-piperidine hydrobromide (Intermediate 32) andcyclopentanone (commercially available) 64 4-[4-(3,5-bis-4-[4-(3,5-bis-trifluoromethyl- 448.5 449.2 trifluoromethyl-phenyl)-phenyl)-thiazol-2-yl]- thiazol-2-yl]-1-cyclopentyl- piperidine;hydrobromide piperidine (Intermediate 33) and cyclopentanone(commercially available)

Example 65 2-(1-Isopropyl-piperidin-4-yl)-thiazole-4-carboxylic acid(4-chloro-phenyl)-amide Step 1: 2-Piperidin-4-yl-thiazole-4-carboxylicacid ethyl ester

A mixture of 10 g (41 mmol) 4-thiocarbamoyl-piperidine-1-carboxylic acidtert-butyl ester (commercially available) and 7.98 g (41 mmol) ethylbromopyruvate (commercially available) in 120 ml ethanol was stirred at70° C. for 90 min. The mixture was evaporated to dryness, Na₂CO₃ aq. wasadded and the residue was extracted with ethyl acetate. The organicphases were washed with NaCl aq., dried with MgSO₄ and evaporated todryness. The residue was purified on silica eluting with DCM/MeOH/25%NH₃ in water 100/20/1 to yield after evaporation of the productfractions 7.28 g (74%) of the title compound as light brown solid.

Step 2: 2-(1-Isopropyl-piperidin-4-yl)-thiazole-4-carboxylic acid ethylester

A mixture of 2 g (8.3 mmol) 2-piperidin-4-yl-thiazole-4-carboxylic acidethyl ester, 0.67 g acetone, 1.2 ml acetic acid and 2.47 g (11.6 mmol)sodium triacetoxyborohydride in 20 ml THF was stirred at 40° C. for 18h. After evaporation to dryness the residue was extracted with 3×250 mlethyl acetate and the combined organic phases were washed with 2×NaHCO₃,NaCl aq., dried with MgSO₄ and evaporated to yield 1.9 g (83%) of thetitle compound of orange solid. (m/e): 283.0 (MH⁺; 100%).

Step 3: 2-(1-Isopropyl-piperidin-4-yl)-thiazole-4-carboxylic acid;hydrochloride

A mixture of 1.9 g (6.7 mmol)2-(1-Isopropyl-piperidin-4-yl)-thiazole-4-carboxylic acid ethyl esterand 5.7 ml HCl aq. (37%) in 13 ml water was stirred at 95° C. for 21 h.The mixture was evaporated to dryness and used without furtherpurification in the consecutive step. (m/e): 255.3 (MH(−HCl)⁺; 100%).

Step 4: 2-(1-Isopropyl-piperidin-4-yl)-thiazole-4-carboxylic acid(4-chloro-phenyl)-amide

A mixture of 29.1 mg (0.1 mmol)2-(1-isopropyl-piperidin-4-yl)-thiazole-4-carboxylic acid;hydrochloride, 35.3 mg (0.11 mmol)2-(1H-benzotriazol-1-yl-1,1,3,3-tetramethyl uronium tetrafluoroborate,14.03 mg (0.11 mol) 4-chloroaniline and 140 ul (0.5 mmol)N-ethyldiisopropylamine in 1 ml DMF was reacted at room temperature fora prolonged period of time. The mixture was treated with 50 μltriethylamine and subjected to preparative HPLC purification on reversedphase material eluting with a gradient ofacetonitrile/water/triethyamine (0.05%). The product fractions wereevaporated to dryness to yield 10.6 mg (29%) of the title compound. MS(m/e): 364.1 (MH⁺, 100%).

Example 66[2-(1-Cyclopentyl-piperidin-4-yl)-thiazol-4-yl]-(2-methyl-pyrrolidin-1-yl)-methanoneStep 1: 2-(1-Cyclopentyl-piperidin-4-yl)-thiazole-4-carboxylic acidethyl ester

According to the procedure described for the synthesis of Example 65b(step 2, (2-(1-isopropyl-piperidin-4-yl)-thiazole-4-carboxylic acidethyl ester) the title compound was synthesized from2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester andcyclopentanone (commercially available). MS (m/e): 309.3 (MH⁺, 100%).

Step 2: 2-(1-Cyclopentyl-piperidin-4-yl)-thiazole-4-carboxylic acid

According to the procedure described for the synthesis of Example 65c(step 3, (2-(1-isopropyl-piperidin-4-yl)-thiazole-4-carboxylic acid) thetitle compound was synthesized from2-piperidin-4-yl-thiazole-4-carboxylic acid ethyl ester. MS (m/e): 281.0(MH⁺, 100%).

Step 3:[2-(1-Cyclopentyl-piperidin-4-yl)-thiazol-4-yl]-(2-methyl-pyrrolidin-1-yl)-methanone

According to the procedure described for the synthesis of Example 65d(step 4, 2-(1-isopropyl-piperidin-4-yl)-thiazole-4-carboxylic acid(4-chloro-phenyl)-amide) the title compound was synthesized from2-(1-cyclopentyl-piperidin-4-yl)-thiazole-4-carboxylic acid and2-methylpyrrolidine. MS (m/e): 348.4 (MH⁺, 100%).

According to the procedure described for the synthesis of Example 66further thiazole amide derivatives have been synthesized from 2-(1-cyclopentyl-piperidin-4-yl)-thiazole-4-carboxylic acid and therespective amine mentioned in Table 3. The examples are compiled inTable 3 and comprise example 67 to example 73.

TABLE 3 MH⁺ Example found No. Name Starting Materials MW (100%) 67[2-(1-cyclopentyl- 2-(1-cyclopentyl-piperidin-4- 361.6 362.3piperidin-4-yl)-thiazol-4- yl)-thiazole-4-carboxylic acidyl]-(3-methyl-piperidin- and 1-yl)-methanone 3-methyl-piperidine(commercially available) 68 [2-(1-cyclopentyl-2-(1-cyclopentyl-piperidin-4- 361.6 362.3 piperidin-4-yl)-thiazol-4-yl)-thiazole-4-carboxylic acid yl]-(2-methyl-piperidin- and1-yl)-methanone 2-methyl-piperidine (commercially available) 69azepan-1-yl-[2-(1- 2-(1-cyclopentyl-piperidin-4- 361.6 362.3cyclopentyl-piperidin-4- yl)-thiazole-4-carboxylic acidyl)-thiazol-4-yl]- and methanone azepane (commercially available) 70[2-(1-cyclopentyl- 2-(1-cyclopentyl-piperidin-4- 395.6 396.3piperidin-4-yl)-thiazol-4- yl)-thiazole-4-carboxylic acidyl]-(3,4-dihydro-1H- and isoquinolin-2-yl)- 3,4-dihydro-1H-isoquinolinemethanone (commercially available) 71 2-(1-cyclopentyl-2-(1-cyclopentyl-piperidin-4- 355.5 356.3 piperidin-4-yl)-thiazole-yl)-thiazole-4-carboxylic acid 4-carboxylic acid and phenylamide aniline(commercially available) 72 2-(1-cyclopentyl-2-(1-cyclopentyl-piperidin-4- 389.9 390.2 piperidin-4-yl)-thiazole-yl)-thiazole-4-carboxylic acid 4-carboxylic acid (4- andchloro-phenyl)-amide 4-chloroaniline (commercially available) 732-(1-cyclopentyl- 2-(1-cyclopentyl-piperidin-4- 385.5 386.3piperidin-4-yl)-thiazole- yl)-thiazole-4-carboxylic acid 4-carboxylicacid (3- and methoxy-phenyl)-amide 3-methoxyaniline (commerciallyavailable)

Example A

Film coated tablets containing the following ingredients can bemanufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula (I) 10.0 mg 200.0 mg Microcrystalline cellulose 23.5 mg 43.5 mg Lactose hydrous 60.0 mg 70.0mg Povidone K30 12.5 mg 15.0 mg Sodium starch glycolate 12.5 mg 17.0 mgMagnesium stearate  1.5 mg  4.5 mg (Kernel Weight) 120.0 mg  350.0 mg Film Coat: Hydroxypropyl methyl cellulose  3.5 mg  7.0 mg Polyethyleneglycol 6000  0.8 mg  1.6 mg Talc  1.3 mg  2.6 mg Iron oxide (yellow) 0.8 mg  1.6 mg Titanium dioxide  0.8 mg  1.6 mg

The active ingredient is sieved and mixed with microcrystallinecellulose and the mixture is granulated with a solution ofpolyvinylpyrrolidone in water. The granulate is mixed with sodium starchglycolate and magnesium stearate and compressed to yield kernels of 120or 350 mg respectively. The kernels are lacquered with an aqueoussolution/suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in aconventional manner:

Ingredients Per capsule Compound of formula (I) 25.0 mg Lactose 150.0mg  Maize starch 20.0 mg Talc  5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula (I) 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Sodiumcarbonate to obtain a final pH of 7 Water for injection solutions ad 1.0ml

Example D

Soft gelatin capsules containing the following ingredients can bemanufactured in a conventional manner:

Capsule contents Compound of formula (I)  5.0 mg Yellow wax  8.0 mgHydrogenated Soya bean oil  8.0 mg Partially hydrogenated plant oils 34.0 mg Soya bean oil 110.0 mg Weight of capsule contents 165.0 mgGelatin capsule Gelatin  75.0 mg Glycerol 85%  32.0 mg Karion 83  8.0 mg(dry matter) Titanium dioxide  0.4 mg Iron oxide yellow  1.1 mg

The active ingredient is dissolved in a warm melting of the otheringredients and the mixture is filled into soft gelatin capsules ofappropriate size. The filled soft gelatin capsules are treated accordingto the usual procedures.

Example E

Sachets containing the following ingredients can be manufactured in aconventional manner:

Compound of formula (I) 50.0 mg Lactose, fine powder 1015.0 mg Microcrystalline cellulose (AVICEL PH 102) 1400.0 mg  Sodiumcarboxymethyl cellulose 14.0 mg Polyvinylpyrrolidone K 30 10.0 mgMagnesium stearate 10.0 mg Flavoring additives  1.0 mg

The active ingredient is mixed with lactose, microcrystalline celluloseand sodium carboxymethyl cellulose and granulated with a mixture ofpolyvinylpyrrolidone in water. The granulate is mixed with magnesiumstearate and the flavoring additives and filled into sachets.

It is to be understood that the invention is not limited to theparticular embodiments of the invention described above, as variationsof the particular embodiments may be made and still fall within thescope of the appended claims.

1. A compound of the formula:

or a pharmaceutically acceptable salt thereof, wherein: R¹ is phenylunsubstituted or substituted with one or two groups independentlyselected from the group consisting of lower alkyl, halogen, lowerhalogenalkyl, lower alkoxy, lower halogenalkoxy, cyano, pyrrolidinyl andlower hydroxyalkyl, R² is hydrogen or lower alkyl; and R³ is isobutyl orcycloalkyl.
 2. A compound according to claim 1, wherein R¹ is phenylsubstituted with one or two groups independently selected from the groupconsisting of lower alkyl, halogen, lower halogenalkyl, lower alkoxy,lower halogenalkoxy, and cyano.
 3. A compound according to claim 1,wherein R¹ is phenyl substituted with one or two groups independentlyselected from the group consisting of halogen, lower halogenalkyl, loweralkoxy, lower halogenalkoxy, and cyano.
 4. A compound according to claim1, wherein R¹ is phenyl substituted with one or two groups independentlyselected from the group consisting of halogen, lower halogenalkyl, loweralkoxy, and lower halogenalkoxy.
 5. A compound according to claim 1,wherein R¹ is phenyl substituted with one or two groups independentlyselected from the group consisting of halogen, lower alkoxy, and lowerhalogenalkoxy.
 6. A compound according to claim 1, wherein R¹ is phenylsubstituted with one or two groups independently selected from the groupconsisting of halogen and lower alkoxy.
 7. A compound according to claim1, wherein R¹ is phenyl substituted with one or two groups independentlyselected from the group consisting of fluoro, chloro, bromo, methoxy,trifluoromethyl, difluoromethoxy, trifluoromethoxy, and cyano.
 8. Acompound according to claim 1, wherein R² is hydrogen.
 9. A compoundaccording to claim 1, wherein R² is lower alkyl.
 10. A compoundaccording to claim 1, wherein R³ is isobutyl.
 11. A compound accordingto claim 1, wherein R³ is cycloalkyl.
 12. A compound according to claim1, wherein R³ is cyclopentyl.
 13. A compound according to claim 1,selected from the group consisting of:1-cyclopentyl-4-(4-phenyl-thiazol-2-yl)-piperidine,4-[4-(3,4-difluoro-phenyl)-thiazol-2-yl]-1-isobutyl-piperidine,1-cyclopentyl-4-[4-(3,4-difluoro-phenyl)-thiazol-2-yl]-piperidine,1-isobutyl-4-[4-(4-methoxy-phenyl)-thiazol-2-yl]-piperidine,1-cyclopentyl-4-[4-(4-methoxy-phenyl)-thiazol-2-yl]-piperidine,4-[4-(2-fluoro-4-methoxy-phenyl)-thiazol-2-yl]-1-isobutyl-piperidine,1-cyclopentyl-4-[4-(2-fluoro-4-methoxy-phenyl)-thiazol-2-yl]-piperidine,1-isobutyl-4-[4-(2-methoxy-phenyl)-thiazol-2-yl]-piperidine,1-cyclopentyl-4-[4-(2-methoxy-phenyl)-thiazol-2-yl]-piperidine,1-isobutyl-4-[4-(2-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine,1-cyclopentyl-4-[4-(2-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine,4-[4-(4-chloro-phenyl)-thiazol-2-yl]-1-isobutyl-piperidine,4-[4-(4-chloro-phenyl)-thiazol-2-yl]-1-cyclopentyl-piperidine,4-[4-(3-fluoro-phenyl)-thiazol-2-yl]-1-isobutyl-piperidine,1-cyclopentyl-4-[4-(3-fluoro-phenyl)-thiazol-2-yl]-piperidine,1-cyclopentyl-4-(5-methyl-4-phenyl-thiazol-2-yl)-piperidine,4-[2-(1-cyclopentyl-piperidin-4-yl)-thiazol-4-yl]-benzonitrile,1-cyclopentyl-4-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine,1-cyclopentyl-4-[4-(3-methoxy-phenyl)-thiazol-2-yl]-piperidine,1-cyclopentyl-4-[4-(4-difluoromethoxy-phenyl)-thiazol-2-yl]-piperidine,3-[2-(1-cyclopentyl-piperidin-4-yl)-thiazol-4-yl]-benzonitrile,1-cyclopentyl-4-[4-(4-trifluoromethoxy-phenyl)-thiazol-2-yl]-piperidine,1-cyclopentyl-4-[4-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine,1-cyclopentyl-4-[4-(3,4-dimethoxy-phenyl)-thiazol-2-yl]-piperidine,4-[4-(4-bromo-phenyl)-5-methyl-thiazol-2-yl]-1-cyclopentyl-piperidine,1-cyclopentyl-4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-piperidine,1-cyclopentyl-4-[4-(2,4-dimethoxy-phenyl)-thiazol-2-yl]-piperidine, and4-[4-(3,5-bis-trifluoromethyl-phenyl)-thiazol-2-yl]-1-cyclopentyl-piperidine,or a pharmaceutically acceptable salt thereof.
 14. A compound accordingto claim 1, selected from the group consisting of:1-cyclopentyl-4-[4-(4-methoxy-phenyl)-thiazol-2-yl]-piperidine,1-cyclopentyl-4-[4-(2-fluoro-4-methoxy-phenyl)-thiazol-2-yl]-piperidine,1-cyclopentyl-4-[4-(2-methoxy-phenyl)-thiazol-2-yl]-piperidine,4-[4-(4-chloro-phenyl)-thiazol-2-yl]-1-cyclopentyl-piperidine,1-cyclopentyl-4-[4-(4-difluoromethoxy-phenyl)-thiazol-2-yl]-piperidine,4-[4-(4-bromo-phenyl)-5-methyl-thiazol-2-yl]-1-cyclopentyl-piperidine,and 1-cyclopentyl-4-[4-(2,4-dimethoxy-phenyl)-thiazol-2-yl]-piperidine,or a pharmaceutically acceptable salt thereof.
 15. A process for themanufacture of a compound according to claim 1, comprising the steps of:reacting a compound of the formula II

wherein R¹ and R² are as defined in claim 1, with an aldehyde or ketoneof the formula IIIR′R″C═O  III wherein R′ is C₁-C₇-alkyl and R″ is C₁-C₆-alkyl or hydrogenor wherein R′ and R″ together with the C atom they are attached to forma cycloalkyl ring, to obtain a compound of the formula I

wherein R¹, R² and R³ are as defined in claim 1, and if desired,converting the compound obtained into a pharmaceutically acceptablesalt.
 16. A pharmaceutical composition, comprising a therapeuticallyeffective amount of a compound according to claim 1 and apharmaceutically acceptable carrier or adjuvant.
 17. A compound selectedfrom the group consisting of:4-[4-(3,4-difluoro-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine,4-[4-(2-fluoro-4-methoxy-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine1-isopropyl-4-[4-(2-methoxy-phenyl)-thiazol-2-yl]-piperidine,4-[4-(2-fluoro-3-trifluoromethyl-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine,4-[2-(1-isopropyl-piperidin-4-yl)-thiazol-4-yl]-benzonitrile,1-isopropyl-4-[4-(4-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine,1-isopropyl-4-[4-(3-methoxy-phenyl)-thiazol-2-yl]-piperidine,4-[4-(4-difluoromethoxy-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine,3-[2-(1-isopropyl-piperidin-4-yl)-thiazol-4-yl]-benzonitrile,1-isopropyl-4-[4-(4-pyrrolidin-1-yl-phenyl)-thiazol-2-yl]-piperidine,1-isopropyl-4-[4-(4-trifluoromethoxy-phenyl)-thiazol-2-yl]-piperidine,1-isopropyl-4-[4-(3-trifluoromethyl-phenyl)-thiazol-2-yl]-piperidine,4-[4-(3,4-dimethoxy-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine,4-[4-(4-bromo-phenyl)-5-methyl-thiazol-2-yl]-1-isopropyl-piperidine,4-[4-(3,4-dichloro-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine, and4-[4-(2,4-dimethoxy-phenyl)-thiazol-2-yl]-1-isopropyl-piperidine, or apharmaceutically acceptable salt thereof.